Substituted imidazo[1,2-b]pyridazines

ABSTRACT

The invention relates to imidazo[1,2-b]pyridazines of general formula (I) a process for their manufacuture and their use for the treatment of benign and malignant neoplasia.

FIELD OF THE INVENTION

The invention relates to imidazo[1,2-b]pyridazines, a process for theirmanufacture and their use for the treatment of benign and malignantneoplasia.

KNOWN TECHNICAL BACKGROUND

Cancer is the second most prevalent cause of death in the United States,causing 450,000 deaths per year. While substantial progress has beenmade in identifying some of the likely environmental and hereditarycauses of cancer, there is a need for additional therapeutic modalitiesthat target cancer and related diseases. In particular there is a needfor therapeutic methods for treating diseases associated withdysregulated growth/proliferation.

Cancer is a complex disease arising after a selection process for cellswith acquired functional capabilities like enhanced survival/resistancetowards apoptosis and a limitless proliferative potential. Thus, it ispreferred to develop drugs for cancer therapy addressing distinctfeatures of established tumors.

One pathway that has been shown to mediate important survival signalsfor mammalian cells comprises receptor tyrosine kinases likeplatelet-derived growth factor receptor (PDGF-R), human epidermal growthfactor 2/3 receptor (HER2/3), or the insulin-like growth factor 1receptor (IGF-1R). After activation the respectives by ligand, thesereceptors activate the phoshatidylinositol 3-kinase (Pi3K)/Akt pathway.The phoshatidylinositol 3-kinase (Pi3K)/Akt protein kinase pathway iscentral to the control of cell growth, proliferation and survival,driving progression of tumors. Therefore within the class ofserine-threonine specific signalling kinases, Akt (protein kinase B;PKB) with the isoenzmyes Akt1 (PKBα), Akt2 (PKB β) and Akt3 (PKB γ) isof high interest for therapeutic intervention. Akt is mainly activatedin a Pi3-kinase dependent manner and the activation is regulated throughthe tumor suppressor PTEN (phosphatase and tensin homolog), which worksessentially as the functional antagonist of Pi3K.

The Pi3K/Akt pathway regulates fundamental cellular functions (e.g.transcription, translation, growth and survival), and is implicated inhuman diseases including diabetes and cancer. The pathway is frequentlyoveractivated in a wide range of tumor entities including breast andprostate carcinomas. Upregulation can be due to overexpression orconstitutively activation of receptor tyrosine kinases (e.g. EGFR,HER2/3), which are upstream and involved in its direct activation, orgain- or loss-of-function mutants of some of the components like loss ofPTEN or mutated PTEN (Michelle M. Hill, Brian A. Hemmings, Pharmacology& Therapeutics 93 (2002) 243-251). The pathway is targeted by genomicalterations including mutation, amplification and rearrangement morefrequently than any other pathway in human cancer, with the possibleexception of the p53 and retinoblastoma pathways. The alterations of thePi3K/Akt pathway trigger a cascade of biological events, that drivetumor progression, survival, angiogenesis and metastasis.

Activation of Akt kinases promotes increased nutrient uptake, convertingcells to a glucose-dependent metabolism that redirects lipid precursorsand amino acids to anabolic processes that support cell growth andproliferation. These metabolic phenotype with overactivated Akt lead tomalignancies that display a metabolic conversion to aerobic glycolysis(the Warburg effect). In that respect the Pi3K/Akt pathway is discussedto be central for survival despite unfavourable growth conditions suchas glucose depletion or hypoxia. A further aspect of the activatedPI3K/Akt pathway is to protect cells from programmed cell death(“apoptosis”) and is hence considered to transduce a survival signal. Byacting as a modulator of anti-apoptotic signalling in tumor cells, thePi3K/Akt pathway, in particular Akt itself is a target for cancertherapy (Constantine S. Mitsiades, Nicholas Mitsiades and MichaelKoutsilieris, Current Cancer Drug Targets, 2004, 4, 235-256). ActivatedAkt phosphorylates and regulates several targets, e.g. BAD. GSK3 orFKHRL1, that affect different signalling pathways like cell survival,protein synthesis or cell movement. This Pi3K/Akt pathway also plays amajor part in resistance of tumor cells to conventional anti-cancertherapies. Blocking the Pi3K/kt pathway could therefore simultaneouslyinhibit the proliferation of tumor cells (e.g. via the inhibition of themetabolic effect) and sensitize towards pro-apoptotic agents.

Akt inhibition selectively sensitized tumor cells to apoptotic stimulilike Trail. Camptothecin and Doxorubicin. Dependent on the geneticbackground/molecular apperations of tumors. Akt inhibitors might induceapoptotic cell death in monotherapy as well.

From WO 2008/070016 tricyclic Akt inhibitors are known which are allegedto be unspecific Akt kinase inhibitors. No data for any specificcompounds are disclosed. Different Akt inhibitors are disclosed in WO2009/021992, WO2010088177, WO2010114780.

In a recent disclosure, Y. Li et al (Bioorg. Med. Chem. Lett. 2009, 19,834-836 and cited references therein) detail the difficulty in findingoptimal Akt inhibitors. The potential application of Akt inhibitors inmultiple disease settings, such as for example, cancer, makes theprovision of further Akt inhibitors in addition to those currentlyavailable highly desirable.

DESCRIPTION OF THE INVENTION

A solution to the above problem is the provision of alternative Aktinhibitors. It has been found that the new substitutedImidazo[1,2-b]pyridazines compounds, which are described in detailbelow, have another profile than the existing AKT-inhibitors.

In accordance with a first aspect, the invention relates to compounds offormula (I)

wherein

-   R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2,    2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl,    2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,        1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9.-   R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl,    -   wherein said 1-6C-alkyl being optionally substituted, one or        more times, identically or differently, with a substituent        selected from: hydroxy, halogen, 1-6C-alkoxy.-   R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,-   R4 is phenyl optionally substituted, one or more times, identically    or differently, with a substituent selected from: 1-6C-alkyl,    halogen, cyano,-   R5 is hydrogen, halogen,-   R6 is hydrogen, 1-6C-alkyl,-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy, or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring,-   R10 is hydrogen, 1-6C-alkyl,-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy) or    3-7C-cycloalkyl,-   X is (CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention are compounds according to claim 1 or2, wherein

-   R1 is hydrogen, halogen, 2-3C-alkenylen-C(O)NH2,    2-3C-alkenylen-C(O)OR10, or a group selected from 1-3C-alkyl,    2-3C-alkenyl, aryl, heteroaryl, wherein said group being optionally    substituted, one or more times, identically or differently, with a    substituent selected from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl,        1-3C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or a group selected from 1-3C-alkyl,    -   wherein said 1-3C-alkyl being optionally substituted, one or        more times, identically or differently, with a substituent        selected from: hydroxy, halogen, 1-3C-alkoxy.-   R3 is hydrogen, 1-3C-alkyl,-   R4 is phenyl optionally substituted, one or more times, identically    or differently, with a substituent selected from: 1-3C-alkyl,    halogen, cyano,-   R5 is hydrogen, halogen.-   R6 is hydrogen, 1-3C-alkyl,-   R8, R9 which can be the same or different, is hydrogen, 1-3C-alkyl.-   R10 is hydrogen, 1-3C-alkyl.-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy).-   X is —(CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds according to claim 1 or 2,wherein

-   R1 is hydrogen, halogen or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,        1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl.    3-7C-cycloalkyl,    -   wherein said 1-6C-alkyl being optionally substituted, one or        more times, identically, or differently, with a substituent        selected from: hydroxy, halogen, 1-6C-alkoxy,-   R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,-   R4 is phenyl optionally substituted, one or more times, identically    or differently, with a substituent selected from: 1-6C-alkyl,    halogen, cyano,-   R5 is hydrogen, halogen,-   R6 is hydrogen, 1-6C-alkyl.-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring,-   R10 is hydrogen, 1-6C-alkyl.-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy) or    3-7C-cycloalkyl,-   X is (CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    -   or an N-oxide, a salt, a tautomer or a stereoisomer of said        compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention are compounds of formula (I) accordingto claim 1, wherein

-   R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2,    2-8C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl,    2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,        1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9.-   R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl,    -   wherein said 1-6C-alkyl being optionally substituted, one or        more times, identically or differently, with a substituent        selected from:    -   hydroxy, halogen, 1-6C-alkoxy, R3 is hydrogen, 1-6C-alkyl,        3-7C-cycloalkyl,-   R4 is phenyl optionally substituted, one or more times, identically    or differently, with a substituent selected from: 1-6C-alkyl,    halogen, cyano,-   R5 is hydrogen, halogen,-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring,-   R10 is hydrogen, 1-6C-alkyl,-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy) or    3-7C-cycloalkyl,-   X is (CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention are compounds of formula (I) accordingto claim wherein

-   R1 is hydrogen, halogen, 2-3C-alkenylen-C(O)NH2,    2-3C-alkenylen-C(O)OR10, or a group selected from 1-3C-alkyl,    2-3C-alkenyl, aryl, heteroaryl, wherein said group being optionally    substituted, one or more times, identically or differently, with a    substituent selected from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl,        1-3C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or a 1-3C-alkyl group,    -   which is optionally substituted, one or more times, identically        or differently, with a substituent selected from:    -   hydroxy, halogen, 1-3C-alkoxy,-   R3 is hydrogen, 1-3C-alkyl,-   R4 is phenyl optionally substituted, one or more times, identically    or differently, with a substituent selected from: 1-3C-alkyl,    halogen, cyano.-   R5 is hydrogen, halogen.-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-3C-alkyl.-   R10 is hydrogen, 1-6C-alkyl,-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy).-   X is (CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer, or stereoisomer.

Another aspect of the invention are compounds of formula (I)

wherein

-   R1 is hydrogen, halogen or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,        1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl,    -   wherein said 1-6C-alkyl being optionally substituted, one or        more times, identically, or differently, with a substituent        selected from: hydroxy, halogen, 1-6C-alkoxy,-   R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,-   R4 is phenyl optionally substituted, one or more times, identically    or differently, with a substituent selected from: 1-6C-alkyl,    halogen, cyano,-   R5 is hydrogen, halogen,-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring,-   R10 is hydrogen, 1-6C-alkyl,-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy) or    3-7C-cycloalkyl,-   X is (CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention are compounds of formula (I) accordingto claim 1 or 2, wherein

-   R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2,    2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl,    2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,        1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl,-   R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,-   R4 is phenyl,-   R5 is hydrogen,-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring,-   R10 is hydrogen, 1-6C-alkyl,-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy) or    3-7C-cycloalkyl,-   X is (CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer, or stereoisomer.

A further aspect of the invention are compounds of formula (I) accordingto claim 1 or 2, wherein

-   R1 is hydrogen, halogen, 2-3C-alkenylen-C(O)NH2,    2-3C-alkenylen-C(O)OR10, or a group selected from 1-3C-alkyl,    2-3C-alkenyl, aryl, heteroaryl, wherein said group being optionally    substituted, one or more times, identically or differently, with a    substituent selected from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl,        1-3C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or a group selected from 1-3C-alkyl,-   R3 is hydrogen, 1-3C-alkyl,-   R4 is phenyl,-   R5 is hydrogen,-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-3C-alkyl-   R10 is hydrogen, 1-3C-alkyl,-   R11 is 1-3C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy),-   X is (CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

A further aspect of the invention are compounds of formula (I)

wherein

-   R1 is hydrogen, halogen or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,        1-6C-alkoxy. —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, S(O)₂R11, —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl,-   R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,-   R4 is phenyl,-   R5 is hydrogen.-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring,-   R10 is hydrogen, 1-6C-alkyl,-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy) or    3-7C-cycloalkyl,-   X is (CH₂)_(n)—,-   n is 0, 1, 2, or 3,-   Y is —CH₂—, —CH(OH)—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer, or stereoisomer.

A further aspect of the invention are compounds of formula (I) accordingto claim 1 or 2,

wherein

-   R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2,    2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl,    2-6C-alkenyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-hydroxyalkyl, cyan(        )—C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)₂R11, —S(O)₂R11,        —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or 1-6C-alkyl,-   R3 is hydrogen,-   R4 is phenyl,-   R5 is hydrogen.-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring,-   R10 is hydrogen, 1-6C-alkyl,-   R11 is 1-4C-alkyl,-   X is (CH₂)_(n)—,-   n is 1,-   Y is —CH₂—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer, or stereoisomer.

A further aspect of the invention are compounds of formula (I) accordingto claim 1 or 2,

wherein

-   R1 is hydrogen, halogen, (2-3C-alkenylen)-C(O)NH2,    -   (2-3C-alkenylen)-C(O)OR10, or a group selected from    -   1-3C-alkyl, 2-3C-alkenyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-hydroxyalkyl, cyano,        —C(O)NR8R9, C(O)OR10, —NHC(O)R11, —NHS(O)₂R11, —S(O)₂R11,        —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or 1-3C-alkyl,-   R3 is hydrogen.-   R4 is phenyl,-   R5 is hydrogen,-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen or    1-3C-alkyl.-   R10 is hydrogen, 1-3C-alkyl.-   R11 is 1-3C-alkyl,-   X is (CH₂)_(n)—,-   n is 1,-   Y is —CH₂—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer, or stereoisomer.

Another aspect of the invention are compounds of formula (I)

wherein,

-   R1 is hydrogen, halogen or a group selected from 1-6C-alkyl, aryl,    heteroaryl, wherein said group being optionally substituted, one or    more times, identically or differently, with a substituent selected    from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-hydroxyalkyl, cyano,        —C(O)NR8R9, C(O)OR10, —NHC(O)R11, —NHS(O)₂R11, —S(O)₂R11,        —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or from 1-6C-alkyl,-   R3 is hydrogen,-   R4 is phenyl,-   R5 is hydrogen.-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring.-   R10 is hydrogen, 1-6C-alkyl,-   R11 is 1-4C-alkyl,-   X is —(CH₂)_(n)—,-   n is 1,-   Y is —CH₂—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer, or stereoisomer.

Another aspect of the invention are compounds of formula (I)

wherein,

-   R1 is hydrogen, halogen or a group selected from 1-3C-alkyl, aryl,    heteroaryl, wherein said group being optionally substituted, one or    more times, identically or differently, with a substituent selected    from:    -   hydroxy, halogen, 1-3C-alkyl, 1-3C-hydroxyalkyl, cyano,        —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)₂R11, —S(O)₂R11,        —S(O)₂NR8R9,-   R2 is hydrogen, halogen, cyano, or a group selected from 1-3C-alkyl.-   R3 is hydrogen,-   R4 is phenyl.-   R5 is hydrogen.-   R6 is hydrogen,-   R8, R9 which can be the same or different, is hydrogen, 1-3C-alkyl    or 3-6C-cycloalkyl, wherein said 1-3C-alkyl and 3-6C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-3C-alkylamino,    1-3C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring.-   R10 is hydrogen, 1-3C-alkyl,-   R11 is 1-3C-alkyl.-   X is (CH₂)_(n)—,-   n is 1,-   Y is —CH₂—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I)

wherein,

-   R1 is hydrogen, halogen, 1-3C-alkyl, 2-3C-alkenyl, —(CH═CH)C(O)NH2,    —(CH═CH)C(O)OR10, pyrazolyl (optionally substituted with methyl),    pyridyl (optionally substituted with hydroxy, methoxy, —C(O)OR10),    indazolyl, phenyl, wherein the phenyl group can optionally be    substituted with a substituent selected from the group consisting of    halogen, methyl, hydroxymethyl, cyano, C(O)NH₂, —C(O)OR10,    —S(O)₂R11, SO₂—NH₂,-   R2 is hydrogen, methyl, halogen (especially chlorine, bromine),-   R3 is hydrogen,-   R4 is phenyl,-   R5 is hydrogen.-   R6 is hydrogen,-   R10 is 1-3C-alkyl,-   R11 is 1-3C-alkyl,-   X is —CH₂—.-   Y is —CH₂—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer, or stereoisomer.

Another aspect of the invention are compounds of formula (I)

wherein,

-   R1 is hydrogen, bromine, methyl, ethyl, —CH═CH2, —(CH═CH)C(O)NH2,    —(CH═CH)C(O)OR10, pyrazolyl (optionally substituted with methyl),    pyridyl (optionally substituted with hydroxy, methoxy, —C(O)OR10    (R10=methyl, ethyl, )), indazolyl, phenyl, wherein the phenyl group    can optionally be substituted with a substituent selected from the    group consisting of    -   fluoro, methyl, hydroxymethyl, cyano, C(O)NH2, —C(O)OR10,        —S(O)₂R11, SO₂—NH₂,-   R2 is hydrogen, methyl, chlorine, bromine,-   R3 is hydrogen.-   R4 is phenyl,-   R5 is hydrogen.-   R6 is hydrogen.-   R10 is methyl,-   R11 is methyl,-   X is —CH₂—,-   Y is —CH₂—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

Another aspect of the invention are compounds of formula (I)

wherein,

-   R1 is hydrogen, bromine, methyl, phenyl, wherein the phenyl group    can optionally be substituted with a substituent selected from the    group consisting of halogen, methyl, hydroxymethyl, cyano,    —C(O)OR10, —S(O)₂R11, SO₂—N(CH₃)₂, SO₂—NH₂,-   R2 is hydrogen.-   R3 is hydrogen,-   R4 is phenyl.-   R5 is hydrogen.-   R6 is hydrogen.-   R10 is methyl.-   R11 is methyl.-   X is —CH₂—.-   Y is —CH₂—,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer, or stereoisomer.

In one aspect of the invention compounds of formula (I) as describedabove are selected from the group consisting of

-   1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,-   1-{4-[3-(4-Methanesulfonylphenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,-   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzoic    acid methyl ester,-   1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-[4-(7-Phenyl-3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   (3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol,-   (4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol    formiate,

A further aspect of the invention are compounds of formula (I) asdescribed above selected from the group consisting of

-   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzenesulfonamide    hydrochloride,-   1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine    hydrochloride,-   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol    hydrochloride,-   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide    hydrochloride,-   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide    hydrochloride,-   1-{4-[7-Phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine    hydrochloride.

A further aspect of the invention are compounds of formula (I) asdescribed above selected from the group consisting of

-   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridin-2-ol-   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridine-2-carboxylic    acid methyl ester,-   1-{4-[7-Phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[3-(1H-Indazol-6-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-nicotinic    acid ethyl ester,-   1-{4-[3-(5-Methoxypyridin-3-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,-   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol,-   1-{4-[2-Methyl-7-phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[3-(4-Fluorophenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,-   1-{4-[2-Methyl-7-phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[2-Methyl-7-phenyl-3-(5-methyl-2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,-   1-[4-(7-Phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine-   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,-   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic    acid methyl ester,-   1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   1-[4-(3-Ethyl-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine

In another aspect of the invention compounds of formula (I) as describedabove are selected from the group consisting of:

-   1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,-   1-{4-[3-(4-Methanesulfonylphenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,-   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzoic    acid methyl ester,-   1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-[4-(7-Phenyl-3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   (3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol,-   (4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol    formiate,-   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzenesulfonamide    hydrochloride,-   1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine    hydrochloride,-   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol    hydrochloride,-   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide    hydrochloride,-   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide    hydrochloride,-   1-{4-[7-Phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine    hydrochloride.-   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridin-2-ol-   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridine-2-carboxylic    acid methyl ester-   1-{4-[7-Phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[3-(1H-Indazol-6-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-nicotinic    acid ethyl ester,-   1-{4-[3-(5-Methoxypyridin-3-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,-   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol,-   1-{4-[2-Methyl-7-phenyl-3-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[3-(4-Fluorophenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,-   1-{4-[2-Methyl-7-phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[2-Methyl-7-phenyl-3-(5-methyl-2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,-   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,-   1-[4-(7-Phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,-   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic    acid methyl ester,-   1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,-   1-[4-(3-Ethyl-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine.

One aspect of the present invention are the compounds disclosed in theexamples as well as the intermediates as used for their synthesis.

One aspect of the invention is intermediate (II) wherein Rx is R6 or aprotecting group Ry is hydrogen or a protecting group, whereby Rx and Rytogether, or Y and Rx together, may form a cyclic protecting group,whereby X, Y, R1, R2, R3, R4, R5 and R6 are defined according to claim 1or preferably Rx is —C(O)OtBu, and Ry is hydrogen.

Another aspect of the invention are compounds of formula (I), wherein

-   R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2,    2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl,    2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,        1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9,

For R1=2-6C-alkenyl, the 2-6C-alkenyl group is preferably unsubstituted,especially vinyl.

-   R1 is hydrogen, halogen or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl, aryl, heteroaryl,    -   wherein said group being optionally substituted, one or more        times, identically or differently, with a substituent selected        from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,        1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,        —NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9.

Another aspect of the invention are compounds of formula (I), wherein

-   R1 is hydrogen, halogen or a group selected from 1-6C-alkyl, aryl,    heteroaryl, wherein said group being optionally substituted, one or    more times, identically or differently, with a substituent selected    from:    -   hydroxy, halogen, 1-6C-alkyl, 1-4C-hydroxyalkyl, cyano,        —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)₂R11, —S(O)₂R11,        —S(O)₂NR8R9.

Another aspect of the invention are compounds of formula (I), wherein

-   R1 hydrogen, 1-3C-alkyl, phenyl (which is optionally substituted    with cyano, methylsulfonyl, methoxycarbonyl, fluorine, methyl,    hydroxymethyl, aminosulfonyl), bromine, pyrazolyl (which is    optionally substituted with methyl), pyridyl (which is optionally    substituted with hydroxy, methoxycarbonyl, ethoxycarbonyl, methoxy),    indazolyl, —CH═CH—C(O)NH2, —CH═CH—C(O)—OCH3, 2-3C-alkenyl.

One aspect of the invention are compounds of formula (I), wherein

-   R1 —CH═CH—C(O)—NH2 or —CH═CH—C(O)—OCH3.

Another aspect of the invention are compounds of formula (I), wherein

-   R1 is hydrogen, bromine, methyl, phenyl, wherein the phenyl group    can optionally be substituted with a substituent selected from the    group consisting of halogen, methyl, hydroxymethyl, cyano,    —C(O)OR10, —S(O)₂R11, SO₂—N(CH₃)₂, SO₂—NH2.

Another aspect of the invention are compounds of formula (I), wherein

-   R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl,    -   wherein said 1-6C-alkyl being optionally substituted, one or        more times, identically or differently, with a substituent        selected from:    -   hydroxy, halogen, 1-6C-alkoxy.

Another aspect of the invention are compounds of formula (I), wherein

-   R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl,    3-7C-cycloalkyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R2 is hydrogen, halogen, cyano, or a group 1-6C-alkyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R2 is hydrogen, methyl, bromine, chlorine.

Another aspect of the invention are compounds of formula (I), wherein

-   R2 is hydrogen.

Another aspect of the invention are compounds of formula (I), wherein

-   R2 is 1-6C-alkyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R2 is methyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R3 is hydrogen.

Another aspect of the invention are compounds of formula (I), wherein

-   R4 is phenyl optionally substituted, one or more times, identically    or differently, with a substituent selected from: 1-6C-alkyl,    halogen, cyano.

Another aspect of the invention are compounds of formula (I), wherein

-   R4 is phenyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R5 is hydrogen, halogen.

Another aspect of the invention are compounds of formula (I), wherein

-   R5 is hydrogen.

Another aspect of the invention are compounds of formula (I), wherein

-   R6 is hydrogen, 1-6C-alkyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R6 is hydrogen.

Another aspect of the invention are compounds of formula (I), wherein

-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is    optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring.

Another aspect of the invention are compounds of formula (I), wherein

-   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl    (optionally substituted in the same way of differently one or more    times with halogen, hydroxy, mono- or di-1-4C-alkylamino,    1-4C-alkoxy), or 3-7C-cycloalkyl,    -   or,    -   in the case of —NR8R9, R8 and R9 together with the nitrogen to        which they are attached may also form a 3-6C-heterocyclic ring.

Another aspect of the invention are compounds of formula (I), wherein

-   R10 is hydrogen, 1-6C-alkyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R10 is methyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R11 is 1-4C-alkyl (optionally substituted in the same way of    differently one or more times with halogen, hydroxy) or    3-7C-cycloalkyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R11 is 1-4C-alkyl.

Another aspect of the invention are compounds of formula (I), wherein

-   R11 is methyl.

Another aspect of the invention are compounds of formula (I), wherein

-   X is (CH₂)_(n)—.

Another aspect of the invention are compounds of formula (I), wherein

-   X is —CH₂—.

Another aspect of the invention are compounds of formula (I), wherein

-   n is 0, 1, 2 or 3.

Another aspect of the invention are compounds of formula (I), wherein

-   n is 0, 1 or 2.

Another aspect of the invention are compounds of formula (I), wherein

-   n is 0 or 1.

Another aspect of the invention are compounds of formula (I), wherein

-   n is 1.

Another aspect of the invention are compounds of formula (I), wherein

-   Y is —CH₂—, —CH(OH)—.

Another aspect of the invention are compounds of formula (I), wherein

-   Y is —CH₂.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R6 is hydrogen and R5 ishydrogen.

In another embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R6 is hydrogen, R5 ishydrogen and R4 is an unsubstituted phenyl moiety.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R5 is hydrogen and R4 is anunsubstituted phenyl moiety.

Another aspect of the invention relates to the group of compoundsobtained by combinations and subcombinations of all residues asdisclosed in the examples.

DEFINITIONS

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, one or more times, independentlyfrom one another at any possible position. When any variable occurs morethan one time in any constituent, each definition is independent.

Unless defined otherwise in the claims the constituents defined belowcan optionally be substituted, one or more times, identically ordifferently, with a substituent selected from:

hydroxy, halogen, cyano, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy,—NR8R9, cyano, (═O), —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)₂R11. Analkyl constituent being substituted more times by halogen includes alsoa completely halogenated alkyl moiety such as e.g. CF3.

Should a constituent be composed of more than one part, e.g.—O-(1-6Calkyl)-3-7C-cycloalkyl, the position of a possible substituentcan be at any of these parts at any suitable position. A hyphen at thebeginning of the constituent marks the point of attachment to the restof the molecule. Should a ring be substituted the substitutent could beat any suitable position of the ring, also on a ring nitrogen atom.

The term “comprising” when used in the specification includes“consisting of”.

If it is referred to “as mentioned above” or “mentioned above” withinthe description it is referred to any of the disclosures made within thespecification in any of the preceding pages.

“suitable” within the sense of the invention means chemically possibleto be made by methods within the knowledge of a skilled person.

If it is referred to “compounds of formula (I)” it is understood that itis referred to compounds of formula (I) as claimed in the compoundclaims.

“1-6C-alkyl” is a straight-chain or branched alkyl group having 1 to 6carbon atoms. Examples are methyl, ethyl, n propyl, iso-propyl, n butyl,iso-butyl, sec-butyl and tert-butyl, pentyl, hexyl, preferably 1-4carbon atoms (1-4C-alkyl), more preferably 1-3 carbon atoms(1-3C-alkyl). Other alkyl constituents mentioned herein having anothernumber of carbon atoms shall be defined as mentioned above taking intoaccount the different length of their chain

“1-4C-Haloalkyl” is a straight-chain or branched alkyl group having 1 to4 carbon atoms in which at least one hydrogen is substituted by ahalogen atom. Examples are chloromethyl or 2-bromoethyl. For a partiallyor completely fluorinated C1-C4-alkyl group, the following partially orcompletely fluorinated groups are considered, for example: fluoromethyl,difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, andpenta-fluoroethyl, whereby fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, or 1,1,1-trifluoroethylare preferred. Partially or completely fluorinated C1-C4-alkyl groupsare considered to be encompassed by the term 1-4C-haloalkyl.

“Mono- or di-1-4C-alkylamino” radicals contain in addition to thenitrogen atom, independently one or two of the above mentioned1-4C-alkyl radicals. Examples are the methyamino, the ethylamino, theisopropylamino, the dimethylamino, the diethylamino and thediisopropylamino radical.

“2-6C-Alkenyl” is a straight chain or branched alkenyl radical having 2to 4 carbon atoms. Examples are the but-2-enyl, but-3-enyl (homoallyl),prop-1-enyl, prop-2-enyl (allyl) and the ethenyl (vinyl) radicals.

“2-6-Alkenylen” is defined as above except that this moiety is bound toother groups/rest of the compound of formula (I) on both sides resultingin spacer position between two groups, e.g. forR1=“2-6-alkenylen-C(O)NH2” the alkenylen group is a spacer between theheterocycle of formula (I) and the group “—C(O)NH2”.

“Halogen” within the meaning of the present invention is iodine,bromine, chlorine or fluorine, preferably “halogen” within the meaningof the present invention is chlorine or fluorine.

“1-4C-Hydroxyalkyl” is a straight-chain or branched alkyl group having 1to 4 carbon atoms whereby the hydroxyl group may be bound at any of thecarbon atoms of the chain. Examples are hydroxymethyl, 1-hydroxyethyl,1-hydroxypropyl, 2-hydroxypropyl, (HO)CH₂—CH(CH₃)—, (CH₃)₂—C(OH)—,1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, hydroxymethyl ispreferred.

“1-6C-Alkoxy” represents radicals, which in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 6 carbonatoms. Examples which may be mentioned are the hexoxy, pentoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pro-poxy, isopropoxy, ethoxy andmethoxy radicals, preferred are methoxy, ethoxy, propoxy, isopropoxy.

“Aryl” represents a mono-, or bicyclic aromatic carbocyclic radicalhaving, as a rule, 6 to 10 carbon atoms; by way of example phenyl ornaphthyl. Phenyl is preferred.

“3-7C-Cycloalkyl” stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, preferably cyclopropyl.

The term “heteroaryl” represents a monocyclic 5- or 6-membered aromaticheterocycle comprised without being restricted thereto, the 5-memberedheteroaryl radicals furyl, thienyl, pyrrolyl, oxa-zolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl(1,2,4-triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl), thiadiazolyl(1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or1,2,4-thiadiazolyl) and oxadiazolyl (1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl), as well asthe 6-membered heteroaryl radicals pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl as well as bicyclic moieties such as e.g. benzofuranyl,benzothienyl, indazolyl, purinyl, chinolinyl, isochinolinyl,phthalazinyl, naphthyridinyl, chinocalinyl, chinazolinyl, cinnolinyl,pteridinyl, indolizinyl, indolyl, isoindolyl. Preferred 5- or 6-memberedheteroaryl radicals are furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl,thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl. More preferred 5- or 6-membered heteroaryl radicals arefuran-2-yl, thien-2-yl, pyrrol-2-yl, thiazolyl, oxazolyl,1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyridin-2-yl, pyridin-4-yl,pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl.Preferred bicyclic radical is indazolyl.

In general and unless otherwise mentioned, the heteroarylic orheteroarylenic radicals include all the possible isomeric forms thereof,e.g. the positional isomers thereof. Thus, for some illustrativenon-restricting example, the term pyridinyl or pyridinylene includespyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene,pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienyleneincludes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

The heteroarylic groups mentioned herein may be substituted by theirgiven substituents or parent molecular groups, unless otherwise noted,at any possible position, such as e.g. at any substitutable ring carbonor ring nitrogen atom. Analogously it is being understood that it ispossible for any heteroaryl group to be attached to the rest of themolecule via any suitable atom if chemically suitable. Unless otherwisenoted, any heteroatom of a heteroarylic ring with unsatisfied valencesmentioned herein is assumed to have the hydrogen atom(s) to satisfy thevalences. Unless otherwise noted, rings containing quaternizable amino-or imino-type ring nitrogen atoms (—N═) may be preferably notquaternized on these amino- or imino-type ring nitrogen atoms by thementioned substituents or parent molecular groups.

In the case of —NR8R9, when R8 and R9 together with the nitrogen atom towhich they are attached form a 3-6C-heterocyclic ring, the term“3-6C-heterocyclic ring” includes all saturated heterocyclic ringscontaining 4 to 7 ring atoms and having 1 or 2 nitrogen atoms, or 1nitrogen atom and 1 oxygen atom. The 3-6C-heterocyclic ring may beoptionally substituted one or more times, identically or differently,with a substituent selected from: 1-4C-alkyl, 1-4C-haloalkyl,1-4C-alkoxy, hydroxy, fluorine, whereby the 1-4C-alkyl may be optionallyfurther substituted with hydroxy. Preferred examples are azetidine,3-hydroxyazetidine, 3-fluoroazetidine, 3,3-difluoroazetidine,pyrrolidine, 3-hydroxypyrrolidine, piperidine, 3-hydroxypiperidine,4-hydroxypiperidine, 3-fluoropiperidine, 3,3-difluoropiperidine,4-fluoropiperidine, 4,4-difluoropiperidine, piperazine,N-methyl-piperazine. N-(2-hydroxyethylypiperazine, morpholine.

The NR8R9 group includes, for example, NH₂, N(H)CH₃, N(CH₃)₂, N(H)CH₂CH₃and N(CH₃)CH₂CH₃. In the case of —NR8R9, when R8 and R9 together withthe nitrogen atom to which they are attached form a 3-6C-heterocyclicring, the term “3-6C-heterocyclic ring” is defined above.

The NH(CO)R11 group includes for example NH(CO)CH₃. NH(CO)C₂H₅,NH(CO)C₃H₇, NH(CO)CH(CH₃)₂.

The NHS(O)₂R11 group includes for example NHS(O)₂CH₃, NHS(O)₂C₂H₅,NHS(O)₂C₃H₇, NHS(O)₂CH(CH₃)₂.

The C(O)NR8R9 group includes, for example, C(O)NH₂, C(O)N(H)CH₃,C(O)N(CH₃)₂, C(O)N(H)CH₂CH₃, C(O)N(CH₃)CH₂CH₃ or C(O)N(CH₂CH₃)₂. In thecase of —NR8R9, when R8 and R9 together with the nitrogen atom to whichthey are attached form a 3-6C-heterocyclic ring, the term“3-6C-heterocyclic ring” is defined above.

The C(O)OR10 group includes for example C(O)OH, C(O)OCH₃, C(O)OC₂H₅,C(O)C₃H₇, C(O)CH(CH₃)₂, C(O)OC₄H₉, C(O)OC₅H₁₁, C(O)OC₆H₁₃; forC(O)O(1-6Calkyl) the alkyl part may be straight or branched.

Salts of the compounds according to the invention include all inorganicand organic acid addition salts and salts with bases, especially allpharmaceutically acceptable inorganic and organic acid addition saltsand salts with bases, particularly all pharmaceutically acceptableinorganic and organic acid addition salts and salts with basescustomarily used in pharmacy.

One aspect of the invention are salts of the compounds according to theinvention including all inorganic and organic acid addition salts,especially all pharmaceutically acceptable inorganic and organic acidaddition salts, particularly all pharmaceutically acceptable inorganicand organic acid addition salts customarily used in pharmacy. Anotheraspect of the invention are the salts with di- and tricarboxylic acids.

Examples of acid addition salts include, but are not limited to,hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, salts ofsulfamic acid, formates, acetates, propionates, citrates, D-gluconates,benzoates, 2-(4-hydroxybenzoyl)-benzoates, butyrates, salicylates,sulfosalicylates, lactates, maleates, laurates, malates, fumarates,succinates, oxalates, malonates, pyruvates, acetoacetates, tartarates,stearates, benzensulfonates, toluenesulfonates, methanesulfonates,trifluoromethansulfonates, 3-hydroxy-2-naphthoates, benzenesulfonates,naphthalinedisulfonates and trifluoroacetates.

Examples of salts with bases include, but are not limited to, lithium,sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine,ammonium, salts optionally derived from NH₃ or organic amines havingfrom 1 to 16 C-atoms such as e.g. ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylendiamine.N-methylpiperindine and guanidinium salts.

The salts include water-insoluble and, particularly, water-solublesalts.

According to the person skilled in the art the compounds of formula (I)according to this invention as well as their salts may contain, e.g.when isolated in crystalline form, varying amounts of solvents. Includedwithin the scope of the invention are therefore all solvates and inparticular all hydrates of the compounds of formula (I) according tothis invention as well as all solvates and in particular all hydrates ofthe salts of the compounds of formula (I) according to this invention.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S,¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The term “another profile” as used in the description of the inventionmeans that the compounds according to the invention possess adifferentiating selectivity to words AKT1 and AKT2.

The term “(chemotherapeutic) anti-cancer agents”, includes but is notlimited to (i) alkylating/carbamylating agents such as Cyclophosphamid(Endoxan®), Ifosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®),Melphalan (Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinumderivatives like cis-platin (Platinex® BMS), oxaliplatin (Eloxatin®),satraplatin or carboplatin (Cabroplat® BMS); (iii) antimitoticagents/tubulin inhibitors such as vinca alkaloids (vincristine,vinblastine, vinorelbine), taxanes such as Paclitaxel (Taxol®),Docetaxel (Taxotere®) and analogs as well as new formulations andconjugates thereof (like the nanoparticle formulation Abraxane® withpaclitaxel bound to albumin), epothilones such as Epothilone B(Patupilone®), Azaepothilone (Ixabepilone®) or Sagopilone; (iv)topoisomerase inhibitors such as anthracyclines (exemplified byDoxorubicin/Adriblastin®), epipodophyllotoxines (examplified byEtoposide/Etopophos®) and camptothecin and camptothecin analogs(exemplified by Irinotecan/Camptosar® or Topotecan/Hycamtin®); (v)pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine(Xeloda®), Arabinosylcytosine Cytarabin (Alexan®) or Gemcitabine(Gemzar®); (vi) purin antagonists such as 6-mercaptopurine(Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and (vii) folicacid antagonists such as methotrexate (Farmitrexat®) or premetrexed(Alimta®).

The term “target specific anti-cancer agent”, includes but is notlimited to (i) kinase inhibitors such as e.g. Imatinib (Glivec®),ZD-1839/Gefitinib (Iressa®), Bay43-9006 (Sorafenib, Nexavar®),SU11248/Sunitinib (Sutent®), OSI-774 Erlotinib (Tarceva®), Dasatinib(Sprycel®), Lapatinib (Tykerb®), or, see also below, Vatalanib,Vandetanib (Zactima®) or Pazopanib; (ii) proteasome inhibitors such asPS-341/Bortezumib (Velcade®); (iii) histone deacetylase inhibitors likeSAHA (Zolinza®), PXD101, MS275, MGCD0103, Depsipeptide/FK228,NVP-LBH589, Valproic acid (VPA), CRA PCI-24781, ITF2357, SB939 andbutyrates (iv) heat shock protein 90 inhibitors like17-allylaminogeldanamycin (17-AAG) or 17-dimethylaminogeldanamycin(17-DMAG); (v) vascular targeting agents (VTAs) like combretastin A4phosphate or AVE8062/AC7700 and anti-angiogenic drugs like the VEGFantibodies, such as Bevacizumab (Avastin®), or KDR tyrosine kinaseinhibitors such as PTK787 ZK222584 (Vatalanib®) or Vandetanib (Zactima®)or Pazopanib; (vi) monoclonal antibodies such as Trastuzumab(Herceptin®), Rituximab (MabThera/Rituxan®), Alemtuzumab (Campath®),Tositumomab (Bexxar®), C225/Cetuximab (Erbitux®), Avastin (see above) orPanitumumab (Vectibix®) as well as mutants and conjugates of monoclonalantibodies, e.g. Gemtuzumab ozogamicin (Mylotarg®) or Ibritumomabtiuxetan (Zevalin®), and antibody fragments; (vii) oligonucleotide basedtherapeutics like G-3139/Oblimersen (Genasense® or the DNMT1 inhibitorMG98; (viii) Toll-like receptor/TLR 9 agonists like Promune®, TLR 7agonists like Imiquimod (Aldara®) or Isatoribine and analogues thereof,or TLR 7/8 agonists like Resiquimod as well as immunostimulatory RNA asTLR 7/8 agonists; (ix) protease inhibitors; (x) hormonal therapeuticssuch as anti-estrogens (e.g. Tamoxifen or Raloxifen), anti-androgens(e.g. Flutamide or Casodex), LHRH analogs (e.g. Leuprolide, Goserelin orTriptorelin) and aromatase inhibitors (e.g. Femara, Arimedex orAromasin).

Other “target specific anti-cancer agents” include bleomycin, retinoidssuch as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitorssuch as 5-Aza-2′-deoxycytidine (Decitabine, Dacogen®) and 5-azacytidine(Vidaza®), alanosine, cytokines such as interleukin-2, interferons suchas interferon α2 or interferon-γ, bcl2 antagonists (e.g. ABT-737 oranalogs), death receptor agonists, such as TRAIL, DR4/5 agonisticantibodies, FasL and TNF-R agonists (e.g. TRAIL receptor agonists likemapatumumab or lexatumumab).

Specific examples of anti-cancer agents include, but are not limited to5 FU, actinomycin D, ABARELIX, ABCIXIMAB, ACLARUBICIN, ADAPALENE,ALEMTUZUMAB, ALTRETAMINE, AMINOGLUTETHIMIDE, AMIPRILOSE, AMRUBICIN,ANASTROZOLE, ANCITABINE, ARTEMISININ, AZATHIOPRINE, BASILIXIMAB,BENDAMUSTINE, BEVACIZUMAB, BEXXAR, BICALUTAMIDE, BLEOMYCIN, BORTEZOMIB,BROXURIDINE, BUSULFAN, CAMPATH, CAPECITABINE, CARBOPLATIN, CARBOQUONE,CARMUSTINE, CETRORELIX, CHLORAMBUCIL, CHLORMETHINE, CISPLATIN,CLADRIBINE, CLOMIFENE, CYCLOPHOSPHAMIDE, DACARBAZINE, DACLIZUMAB,DACTINOMYCIN, DASATINIB, DAUNORUBICIN, DECITABINE, DESLORELIN,DEXRAZOXANE, DOCETAXEL, DOXIFLURIDINE, DOXORUBICIN, DROLOXIFENE,DROSTANOLONE, EDELFOSINE, EFLORNITHINE, EMITEFUR, EPIRUBICIN,EPITIOSTANOL, EPTAPLATIN, ERBITUX, ERLOTINIB, ESTRAMUSTINE, ETOPOSIDE,EXEMESTANE, FADROZOLE, FINASTERIDE, FLOXURIDINE, FLUCYTOSINE,FLUDARABINE, FLUOROURACIL, FLUTAMIDE, FORMESTANE, FOSCARNET, FOSFESTROL,FOTEMUSTINE, FULVESTRANT, GEFITINIB, GENASENSE, GEMCITABINE, GLIVEC,GOSERELIN, GUSPERIMUS, HERCEPTIN, IDARUBICIN, IDOXURIDINE, IFOSFAMIDE,IMATINIB, IMPROSULFAN, INFLIXIMAB, IRINOTECAN, IXABEPILONE, LANREOTIDE,LAPATINIB, LETROZOLE, LEUPRORELIN, LOBAPLATIN, LOMUSTINE, LUPROLIDE,MELPHALAN, MERCAPTOPURINE, METHOTREXATE, METUREDEPA, MIBOPLATIN,MIFEPRISTONE, MILTEFOSINE, MIRIMOSTIM, MITOGUAZONE, MITOLACTOL,MITOMYCIN, MITOXANTRONE, MIZORIBINE, IVIOTEXAFIN, MYLOTARG,NARTOGRASTIM, NEBAZUMAB, NEDAPLATIN, NILUTAMIDE, NIMUSTINE, OCTREOTIDE,ORMELOXIFENE, OXALIPLATIN. PACLITAXEL, PALIVIZUMAB, PANITUMUMAB,PATUPILONE, PAZOPANIB, PEGASPARGASE, PEGFILGRASTIM, PEMETREXED,PENTETREOTIDE, PENTOSTATIN, PERFOSFAMIDE, PIPOSULFAN, PIRARUBICIN,PLICAMYCIN, PREDNIMUSTINE, PROCARBAZINE, PROPAGERMANIUM, PROSPIDIUMCHLORIDE, RALOXIFEN, RALTITREXED, RANIMUSTINE, RANPIRNASE, RASBURICASE,RAZOXANE, RITUXIMAB, RIFAMPICIN, RITROSULFAN, ROMURTIDE, RUBOXISTAURIN,SAGOPILONE, SARGRAMOSTIM, SATRAPLATIN, SIROLIMUS, SOBUZOXANE, SORAFENIB,SPIROMUSTINE, STREPTOZOCIN, SUNITINIB, TAMOXIFEN, TASONERMIN, TEGAFUR,TEMOPORFIN, TEMOZOLOMIDE, TENIPOSIDE, TESTOLACTONE, THIOTEPA,THYMALFASIN, TIAMIPRINE, TOPOTECAN, TOREMIFENE, TRAIL, TRASTUZUMAB,TREOSULFAN, TRIAZIQUONE, TRIMETREXATE, TRIPTORELIN, TROFOSFAMIDE,UREDEPA, VALRUBICIN, VATALANIB, VANDETANIB, VERTEPORFIN, VINBLASTINE,VINCRISTINE, VINDESINE, VINORELBINE, VOROZOLE, ZEVALIN and ZOLINZA.

The compounds according to the invention and their salts can exist inthe form of tautomers which are included in the embodiments of theinvention.

The compounds of the invention may, depending on their structure, existin different stereoisomeric forms. These forms include configurationalisomers or optionally conformational isomers (enantiomers and/ordiastereoisomers including those of atropisomers). The present inventiontherefore includes enantiomers, diastereoisomers as well as mixturesthereof. From those mixtures of enantiomers and/or disastereoisomerspure stereoisomeric forms can be isolated with methods known in the art,preferably methods of chromatography, especially high pressure liquidchromatography (HPLC) using achiral or chiral phase. The inventionfurther includes all mixtures of the stereoisomers mentioned aboveindependent of the ratio, including the racemates.

Some of the compounds and salts according to the invention may exist indifferent crystalline forms (polymorphs) which are within the scope ofthe invention.

Furthermore, derivatives of the compounds of formula (I) and the saltsthereof which are converted into a compound of formula (I) or a saltthereof in a biological system (bioprecursors or pro-drugs) are coveredby the invention. Said biological system is e.g. a mammalian organism,particularly a human subject. The bioprecursor is, for example,converted into the compound of formula (I) or a salt thereof bymetabolic processes.

The intermediates used for the synthesis of the compounds of claims 1-5as described below, as well as their use for the synthesis of thecompounds of claims 1-5, are one further aspect of the presentinvention. Preferred intermediates are intermediate of formula (II) aswell as the Intermediate Examples as disclosed below.

The compounds according to the invention can be prepared according tothe following schemes:

The compounds according to the invention can be prepared according toreaction scheme 1 wherein X, Y, R1, R2*), R3, R4, R5 and R6 have themeanings defined in claim 1; Rx has the meaning of R6 and may also be aprotecting group: Ry is H, or a protecting group, whereby Rx and Rytogether, or Y and Rx together, may form a cyclic protecting group; Halis a halogen; Xa is a leaving group such as halogen, or a sulfonylester, preferably Cl, Br, I, OTs, OTf, or ONf; M is —B(OH)₂,Sn(1-4C-alkyl)₃, ZnCl, ZnBr, ZnI, or,

Compounds of general formula (I) may be prepared from compounds ofgeneral formula (II). Rx may optionally be R6, or a protecting group, orother such precursor which requires further manipulation. For example,Rx in compounds of general formula (II) may be a protecting group suchas the Boc group, —CO(OtBu), or Rx and Ry, together with the nitrogen towhich they are attached, form a cyclic protecting group such as aphthalimide. Preparation of compounds of general formula (I) may thus beaccomplished by use of an appropriate deprotection reaction, such as inthe case of a Boc group, acidic reaction conditions, for example, with asolution of 4M hydrogen chloride in dioxane, in an appropriate solvent,such as for example DCM and methanol, at ambient temperature. Furtherconditions to deprotect the Boc group, or further protecting groups thatmay be suitable for use in blocking the amino functionality in compoundsof general formula (II), including their synthesis and deprotection, arefound, for example, in T. W. Greene, Protective Groups in OrganicSynthesis, John Wiley & Sons, 1999, 3rd Ed., or in P. Kocienski,Protecting Groups, Thieme Medical Publishers, 2000. Similarly, when Ryis not H, then Ry is a protecting group, such as for example when Rx andRy together form a cyclic protecting group such as for example aphthalamide.

Compounds of general formula (II) may be prepared by reacting a compoundof general formula (III) with a compound R-M, for example by atransition metal catalysed C—C bond formation. The transition metalcatalysed C—C bond formation reaction can, for example, be achieved if Mhas the meaning of,

and Xa is Cl, in a suitable solvent such as THF, NMP, DMF, DME, dioxaneor mixtures of the above, in the presence of a suitable base, such asaqueous sodium carbonate or potassium carbonate solution, at a suitabletemperature, such as from 60° C. to 120° C. and by employing a suitablemetal catalyst, such as a palladium catalyst, for example1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)[Pd(dppf)Cl₂], bis(tri-tert.-butylphosphin)palladium(0) [Pd(PtBu₃)₂], orPd(PPh₃)₄.

Compounds of general formula (III) may be prepared by introducing aleaving group Xa into a compound of general formula (IV). Thistransformation can, for example, be achieved by reacting a compound ofgeneral formula (IV) with N-bromosuccinimide or N-chlorosuccinimide.However, this transformation is restricted to compounds in which R2 is Hor alkyl or cycloalkyl.

*) R2=halogen is introduced in compounds in which R1 is not hydrogen, asan example reference is made to examples 6 and 7.

Compounds of general formula (IV) may be prepared by reacting a compoundof general formula (V) with a compound of general formula (VI), forexample by a transition metal catalysed C—C bond formation. Thetransition metal catalysed C—C bond formation reaction can, for example,be achieved if M has the meaning of,

and Xa is Cl, in a suitable solvent such as THF, NMP, DMF, DME, dioxaneor mixtures of the above, in the presence of a suitable base, such asaqueous sodium carbonate or potassium carbonate solution, at a suitabletemperature, such as from 60° C. to 120° C. and by employing a suitablemetal catalyst, such as a palladium catalyst, for example1,1′-bis(diphenylphosphino)ferroceneldichloropalladium(II)[Pd(dppf)Cl₂], bis(tri-tert.-butylphosphin)palladium(0) [Pd(PtBu₃)₂], orPd(PPh₃)₄.

Compounds of general formula (VI) may be prepared from compounds ofgeneral formula (VII) using known methods, for example, if M has themeaning of

by way of a palladium catalysed borylation reaction, using a suitablemetal complex such as a palladium complex formed in situ from a suitablepalladium salt and a suitable phosphine ligand, for example,PdCl₂(CH₃CN)₂ and SPhos (CAS 657408-07-6), or a preformed palladiumcomplex such as a suitable boron reagent, such as pinacol borane, orbis(pinacolato)diboron (CAS 73183-34-3), a suitable solvent, such asdioxane, DMSO, or THF, and elevated temperatures, such as up to theboiling point of the solvent, preferably 80-120° C. An analogueprocedure for the palladium catalysed borylation of aryl halides usingpinacol borane is reported by Buchwald et al in J. Org. Chem. 2008,p5589. Alternatively, borylation may be achieved by halogen-metalexchange, followed by quenching of the anion with a suitable borateester. For example, compounds of general formula (VII) may be reactedwith 2 Eq of sec-butyl lithium or n-butyl lithium in a suitable solventsuch as THF, at suitable temperature, such as from −78° C. to 20° C.,preferably from −78° C. to −50° C., followed by reaction with methylpinacol borate or isopropyl pinacol borate. Analogous procedures areknown in the literature, such as in EP1870099.

Compounds of general formula (VII) and (VIII) are either commerciallyavailable, may be prepared using the methods described below, may beprepared using known methods, or may be prepared by analogous methods tothose known by the person skilled in the art.

One aspect of the invention is the reaction of compounds of generalformulae (V) and (VI) followed by introduction of a leaving group toform a compound of general formula (III). A further aspect is theintroduction of R1 to form a compound of general formula (II) as well asdeprotection of the compound of general formula (II) to form a compoundof general formula (I).

Compounds of general formula (V) may be prepared according to reactionscheme 2 by reaction of (IX) with a compound (XIII), wherein R2, R3 andR4 have the meanings defined above; Ka and Xb are halogen. The compounds(XIII) are commercially available. The compounds of general formula (V)and (IX) and (XIII) are described in US 2007/0078136 (WO2007/1038314) aswell.

Another aspect of the invention is the intermediate of general formula(III)

wherein

-   Rx is R6 or a protecting group-   Ry is hydrogen or a protecting group.    -   whereby Rx and Ry together, or Y and Rx together, may form a        cyclic protecting group,        whereby X, Y, R1, R2, R3, R4, R5 and R6 are defined according to        claim 1 as well as its use for the production of the compounds        of general formula (I).

It is known to the person skilled in the art that, if there are a numberof reactive centers on a starting or intermediate compound, it may benecessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999,3rd Ed., or in P. Kocienski, Protecting Groups, Thieme MedicalPublishers, 2000.

The compounds according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such aschromatography on a suitable support material. Furthermore, reversephase preparative HPLC of compounds of the present invention whichpossess a sufficiently basic or acidic functionality, may result in theformation of a salt, such as, in the case of a compound of the presentinvention which is sufficiently basic, a trifluoroacetate or formatesalt for example, or, in the case of a compound of the present inventionwhich is sufficiently acidic, an ammonium salt for example. Salts ofthis type can either be transformed into its free base or free acidform, respectively, by various methods known to the person skilled inthe art, or be used as salts in subsequent biological assays.Additionally, the drying process during the isolation of compounds ofthe present invention may not fully remove traces of cosolvents,especially such as formic acid or trifluoroacetic acid, to give solvatesor inclusion complexes. The person skilled in the art will recognisewhich solvates or inclusion complexes are acceptable to be used insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base, solvate, inclusion complex) of a compound ofthe present invention as isolated as described herein is not necessarilythe only form in which said compound can be applied to a biologicalassay in order to quantify the specific biological activity.

Salts of the compounds of formula (I) according to the invention can beobtained by dissolving the free compound in a suitable solvent (forexample a ketone such as acetone, methylethylketone ormethylisobutylketone, an ether such as diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol such asmethanol, ethanol or isopropanol) which contains the desired acid orbase, or to which the desired acid or base is then added. The acid orbase can be employed in salt preparation, depending on whether a mono-or polybasic acid or base is concerned and depending on which salt isdesired, in an equimolar quantitative ratio or one differing therefrom.The salts are obtained by filtering, reprecipitating, precipitating witha non-solvent for the salt or by evaporating the solvent. Salts obtainedcan be converted into the free compounds which, in turn, can beconverted into salts. In this manner, pharmaceutically unacceptablesalts, which can be obtained, for example, as process products in themanufacturing on an industrial scale, can be converted intopharmaceutically acceptable salts by processes known to the personskilled in the art.

Pure diastereomers and pure enantiomers of the compounds and saltsaccording to the invention can be obtained e.g. by asymmetric synthesis,by using chiral starting compounds in synthesis and by splitting upenantiomeric and diasteriomeric mixtures obtained in synthesis.

Enantiomeric and diastereomeric mixtures can be split up into the pureenantiomers and pure diastereomers by methods known to a person skilledin the art. Preferably, diastereomeric mixtures are separated bycrystallization, in particular fractional crystallization, orchromatography. Enantiomeric mixtures can be separated e.g. by formingdiastereomers with a chiral auxiliary agent, resolving the diastereomersobtained and removing the chiral auxiliary agent. As chiral auxiliaryagents, for example, chiral acids can be used to separate enantiomericbases such as e.g. mandelic acid and chiral bases can be used toseparate enantiomeric acids via formation of diastereomeric salts.Furthermore, diastereomeric derivatives such as diastereomeric esterscan be formed from enantiomeric mixtures of alcohols or enantiomericmixtures of acids, respectively, using chiral acids or chiral alcohols,respectively, as chiral auxiliary agents. Additionally, diastereomericcomplexes or diastereomeric clathrates may be used for separatingenantiomeric mixtures. Alternatively, enantiomeric mixtures can be splitup using chiral separating columns in chromatography. Another suitablemethod for the isolation of enantiomers is the enzymatic separation.

One preferred aspect of the invention is the process for the preparationof the compounds of claims 1-5 according to the examples.

Optionally, compounds of the formula (I) can be converted into theirsalts, or, optionally, salts of the compounds of the formula (I) can beconverted into the free compounds. Corresponding processes are customaryfor the skilled person.

Optionally, compounds of the formula (I) can be converted into theirN-oxides. The N-oxide may also be introduced by way of an intermediate.N-oxides may be prepared by treating an appropriate precursor with anoxidizing agent, such as meta-chloroperbenzoic acid, in an appropriatesolvent, such as dichloromethane, at suitable temperatures, such as from0° C. to 40° C., whereby room temperature is generally preferred.Further corresponding processes for forming N-oxides are customary forthe skilled person.

Commercial Utility

The compounds of formula (I) and the stereoisomers of the compounds offormula (I) according to the invention are hereinafter referred to asthe compounds of the invention. In particular, the compounds of theinvention are pharmaceutically acceptable. The compounds according tothe invention have valuable pharmaceutical properties, which make themcommercially utilizable. In particular, they inhibit the Pi3K/Aktpathway and exhibit cellular activity. They are expected to becommercially applicable in the therapy of diseases (e.g. diseasesdependent on overactivated Pi3K/Akt). An abnormal activation of thePI3K/AKT pathway is an essential step towards the initiation andmaintenance of human tumors and thus its inhibition, for example withAKT inhibitors, is understood to be a valid approach for treatment ofhuman tumors. For a recent review see Garcia-Echeverria et al (Oncogene,2008, 27, 551-5526).

Cellular activity and analogous terms in the present invention is usedas known to persons skilled in the art, as an example, inhibition ofphosphorylation, inhibition of cellular proliferation, induction ofapoptosis or chemosensitization.

Chemosensitization and analogous terms in the present invention is usedas known to persons skilled in the art. These stimuli include, forexample, effectors of death receptor and survival pathways as well ascytotoxic/chemotherapeutic and targeted agents and finally radiationtherapy. Induction of apoptosis and analogous terms according to thepresent invention are used to identify a compound which executesprogrammed cell death in cells contacted with that compound or incombination with other compounds routinely used for therapy.

Apoptosis in the present invention is used as known to persons skilledin the art. Induction of apoptosis in cells contacted with the compoundof this invention might not necessarily be coupled with inhibition ofcell proliferation. Preferably, the inhibition of proliferation and/orinduction of apoptosis are specific to cells with aberrant cell growth.

Furthermore, the compounds according to the present invention inhibitprotein kinase activity in cells and tissues, causing a shift towardsdephosphorylated substrate proteins and as functional consequence, forexample the induction of apoptosis, cell cycle arrest and/orsensitization towards chemotherapeutic and target-specific cancer drugs.In a preferred embodiment, inhibition of the Pi3K/Akt pathway inducescellular effects as mentioned herein, alone, or in combination withstandard cytotoxic or targeted cancer drugs.

In addition inhibition of AKT signaling pathway was found to inhibitretinal neovascularisation in the oxygene induced retinopathy model aswell as a potential therapeutic use of a AKT inhibition on choroidalneovascularisation was shown (Wang et al., Acta Histochem. Cytochem.44(2): 103-111, 2011; Yang et al., Investigative Ophthalmology & VisualScience (IOVS), April 2009, Vol. 50, No. 4) These results lead to theconclusion that AKT inhibition could provide a useful therapy for oculardiseases associated with ocular neovascularisation like e.g. Age RelatedMacula Degeneration (AMD), Macula Degeneration (MD) und diabeticretinopathy.

Thus one embodiment of the invention includes methods of treatment ofocular diseases associated with ocular neovasculariation especially AMD,MD und diabetic retinopathy comprising administering a compound ofgeneral formula (I) as well as the use of those compounds for thetreatment of said diseases.

Compounds according to the present invention exhibit anti-proliferativeand/or pro-apoptotic and/or chemosensitizing properties. Accordingly,the compounds of the present invention are useful for the treatment ofhyperproliferative disorders, in particular cancer. Therefore thecompounds of the present invention are useful to induce ananti-proliferative and/or pro-apoptotic and/or chemosensitizing effectin mammals, such as humans, suffering from a hyperproliferativedisorders, like cancer.

The invention further relates to a compound according to the inventionor a pharmaceutically acceptable salt thereof, for the treatment and/orprophylaxis, preferably treatment of (hyper)proliferative diseasesand/or disorders responsive to induction of apoptosis, which includebenign neoplasia and malignant neoplasia, especially malignantneoplasia, including cancer and the tumor types as disclosed below.

Compounds according to the present invention exhibit anti-proliferativeand/or pro-apoptotic properties in mammals such as humans due toinhibition of metabolic activity of cancer cells which are able tosurvive despite of unfavourable growth conditions such as glucosedepletion, hypoxia or other chemo stress.

Thus, the compounds according to the present invention are useful fortreating, ameliorating or preventing diseases of benign or malignantbehaviour as described herein, such as e.g. for inhibiting cellularneoplasia.

Neoplasia in the present invention is used as known to persons skilledin the art. A benign neoplasia is described by hyperproliferation ofcells, incapable of forming an aggressive, metastasizing tumor in-vivo.In contrast, a malignant neoplasia is described by cells with multiplecellular and biochemical abnormalities, capable of forming a systemicdisease, for example forming tumor metastasis in distant organs.

The compounds according to the present invention can be preferably usedfor the treatment of malignant neoplasia. Examples of malignantneoplasia treatable with the compounds according to the presentinvention include solid and hematological tumors. Solid tumors can beexemplified by tumors of the breast, bladder, bone, brain, central andperipheral nervous system, colon, endocrine glands (e.g. thyroid andadrenal cortex), esophagus, endometrium, germ cells, head and neck,kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary,pancreas, prostate, rectum, renal, small intestine, soft tissue, testis,stomach, skin, ureter, vagina and vulva. Malignant neoplasias includeinherited cancers exemplified by Retinoblastoma and Wilms tumor. Inaddition, malignant neoplasias include primary tumors in said organs andcorresponding secondary tumors in distant organs (“tumor metastases”).Hematological tumors can be exemplified by aggressive and indolent formsof leukemia and lymphoma, namely non-Hodgkins disease, chronic and acutemyeloid leukemia (CML AML), acute lymphoblastic leukemia (ALL), Hodgkinsdisease, multiple myeloma and T-cell lymphoma. Also included aremyelodysplastic syndrome, plasma cell neoplasia, paraneoplasticsyndromes, and cancers of unknown primary site as well as AIDS relatedmalignancies.

It is noted that a malignant neoplasia does not necessarily require theformation of metastases in distant organs. Certain tumors exertdevastating effects on the primary organ itself through their aggressivegrowth properties. These can lead to the destruction of the tissue andorgan structure finally resulting in failure of the assigned organfunction and death.

Drug resistance is of particular importance for the frequent failure ofstandard cancer therapeutics. This drug resistance is caused by variouscellular and molecular mechanisms. One aspect of drug resistance iscaused by constitutive activation of anti-apoptotic survival signalswith PKB/Akt as a key signalling kinase. Inhibition of the Pi3K/Aktpathway leads to a resensitization towards standard chemotherapeutic ortarget specific cancer therapeutics. As a consequence, the commercialapplicability of the compounds according to the present invention is notlimited to 1^(st) line treatment of cancer patients. In a preferredembodiment, cancer patients with resistance to cancer chemotherapeuticsor target specific anti-cancer drugs are also amenable for treatmentwith these compounds for e.g. 2^(nd) or 3^(rd) line treatment cycles. Inparticular, the compounds according to the present invention might beused in combination with standard chemotherapeutic or targeted drugs toresensitize tumors towards these agents.

Compounds according to the present invention are suitable for treatment,prevention or amelioration of the diseases of benign and malignantbehavior as described above, such as e.g. benign or malignant neoplasia,particularly cancer, especially a cancer that is sensitive to Pi3K/Aktpathway inhibition.

The present invention further includes a method for treating, preventingor ameliorating mammals, including humans, preferably treating mammals,including humans, which are suffering from one of the abovementionedconditions, illnesses, disorders or diseases. The method ischaracterized in that a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention is administered to the subject in need of suchtreatment.

The present invention further includes a method for treating, preventingor ameliorating diseases responsive to inhibition of the Pi3K/Aktpathway, in a mammal, including human, preferably treating diseasesresponsive to inhibition of the Pi3K/Akt pathway, in a mammal, includinghuman, comprising administering a pharmacologically active andtherapeutically effective and tolerable amount of one or more of thecompounds according to the present invention to said mammal.

The present invention further includes a method for inhibiting proteinkinase activity in cells comprising administering a pharmacologicallyactive and therapeutically effective and tolerable amount of one or moreof the compounds according to the present invention to a patient in needof such therapy.

The present invention further includes a method for treatinghyperproliferative diseases of benign or malignant behaviour and/ordisorders responsive to induction of apoptosis, such as e.g. cancer,particularly any of those cancer diseases described above, in a mammal,comprising administering a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention to said mammal.

The present invention further includes a method for inhibiting cellularhyperproliferation or arresting aberrant cell growth in a mammal,comprising administering a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention to said mammal.

The present invention further includes a method for inducing apoptosisin the therapy of beningn or malignant neoplasia, particularly cancer,comprising administering a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention to a subject in need of such therapy.

The present invention further includes a method for inhibiting proteinkinase activity in cells comprising administering a pharmacologicallyactive and therapeutically effective and tolerable amount of one or moreof the compounds according to the present invention to a patient in needof such therapy.

The present invention further includes a method for sensitizing towardschemotherapeutic or target-specific anti-cancer agents in a mammal,comprising administering a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention to said mammal.

The present invention further includes a method for treating benignand/or malignant neoplasia, especially malignant neoplasia, particularlycancer, in a mammal, including human, comprising administering apharmacologically active and therapeutically effective and tolerableamount of one or more of the compounds according to the presentinvention to said mammal.

The present invention further includes a method for treating solid andhematological tumors, whereby solid tumors can be exemplified by tumorsof the breast, bladder, bone, brain, central and peripheral nervoussystem, colon, endocrine glands (e.g. thyroid and adrenal cortex),esophagus, endometrium, germ cells, head and neck, kidney, liver, lung,larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum,renal, small intestine, soft tissue, testis, stomach, skin, ureter,vagina and vulva. Malignant neoplasias include inherited cancersexemplified by Retinoblastoma and Wilms tumor. In addition, malignantneoplasias include primary tumors in said organs and correspondingsecondary tumors in distant organs (“tumor metastases”). andhematological tumors can be exemplified by aggressive and indolent formsof leukemia and lymphoma, namely non-Hodgkins disease, chronic and acutemyeloid leukemia (CML AML), acute lymphoblastic leukemia (ALL). Hodgkinsdisease, multiple myeloma and T-cell lymphoma. Also included aremyelodysplastic syndrome, plasma cell neoplasia, paraneoplasticsyndromes, and cancers of unknown primary site as well as AIDS relatedmalignancies.

The present invention further relates to the use of the compounds forthe production of pharmaceutical compositions, which are employed forthe treatment, prophylaxis, and/or amelioration of one or more of theillnesses mentioned, preferably for the treatment of one or more of theillnesses mentioned.

The present invention further relates to the use of the compounds forthe manufacture of pharmaceutical compositions for treating, preventingor ameliorating, preferably treating hyperproliferative diseases and/ordisorders responsive to the induction of apoptosis, such as e.g. beningnor malignant neoplasia, especially malignant neoplasia, in particularcancer, especially those cancer diseases and tumor types mentionedabove.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions for treating, preventing or ameliorating, preferablytreating benign or malignant neoplasia, especially malignant neoplasia,particularly cancer, such as e.g. any of those cancer diseases and tumortypes described above.

The invention further relates to a compound according to the inventionor a pharmaceutically acceptable salt thereof, for the treatment and/orprophylaxis, preferably treatment of diseases, especially for thetreatment and/or prophylaxis, preferably treatment of(hyper)proliferative diseases and/or disorders responsive to inductionof apoptosis, which include benign neoplasia and malignant neoplasia,including cancer.

The invention further related to the use of a compound according to theinvention or a pharmaceutically acceptable salt thereof, for theproduction of a pharmaceutical composition for the treatment, preventionor amelioration of a disease mediated by a dysregulated function of asingle protein kinase or multiple protein kinases and/or disordersresponsive to the induction of apoptosis.

The invention further relates to a pharmaceutical composition comprisingat least one compound of general formula (I) according to any of claims1 to 6, together with at least one pharmaceutically acceptable auxiliary

The invention in addition relates to a pharmaceutical composition,comprising a compound according to the invention or a pharmaceuticallyacceptable salt thereof, for the treatment and/or prophylaxis,preferably treatment of (hyper)proliferative diseases and/or disordersresponsive to induction of apoptosis, which include benign neoplasia andmalignant neoplasia, including cancer.

The present invention further relates to the use of compounds andpharmaceutically acceptable salts according to the present invention forthe manufacture of pharmaceutical compositions, which can be used forsensitizing towards chemotherapeutic and/or target specific anti-canceragents.

The present invention further relates to the use of compounds accordingto the present invention for the manufacture of pharmaceuticalcompositions, which can be used for sensitizing towards radiationtherapy of those diseases mentioned herein, particularly cancer.

The present invention further relates to the use of the compoundsaccording to the present invention for the manufacture of pharmaceuticalcompositions, which can be used in the treatment of diseases sensitiveto protein kinase inhibitor therapy and different to cellular neoplasia.These non-malignant diseases include, but are not limited to benignprostate hyperplasia, neurofibromatosis, dermatoses, and myelodysplasticsyndromes.

The present invention further relates to pharmaceutical compositionscomprising one or more of the compounds according to this invention anda pharmaceutically acceptable carrier or diluent.

The present invention further relates to pharmaceutical compositionscomprising one or more of the compounds according to this invention andpharmaceutically acceptable auxiliaries and/or excipients.

The pharmaceutical compositions according to this invention are preparedby processes, which are known per se and familiar to the person skilledin the art. As pharmaceutical compositions, the compounds of theinvention (=active compounds) are either employed as such, or preferablyin combination with suitable pharmaceutical auxiliaries and/orexcipients, e.g. in the form of tablets, coated tablets, dragees, pills,cachets, granules, capsules, caplets, suppositories, patches (e.g. asTTS), emulsions (such as e.g. micro-emulsions or lipid emulsions),suspensions (such as e.g. nano suspensions), gels, solubilisates orsolutions (e.g. sterile solutions), or encapsuled in liposomes or asbeta-cyclodextrine or beta-cyclodextrin derivative inclusion complexesor the like, the active compound content advantageously being between0.1 and 95% and where, by the appropriate choice of the auxiliariesand/or excipients, a pharmaceutical administration form (e.g. a delayedrelease form or an enteric form) exactly suited to the active compoundand/or to the desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, vehicles,excipients, diluents, carriers or adjuvants which are suitable for thedesired pharmaceutical formulations, preparations or compositions onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers (such as e.g. polyoxyethylenglyceroltriricinoleat 35, PEG400, Tween 80, Captisol, Solutol HS15 or the like), colorants,complexing agents, permeation promoters, stabilizers, fillers, binders,thickeners, disintegrating agents, buffers, pH regulators (e.g. toobtain neutral, alkaline or acidic formulations), polymers, lubricants,coating agents, propellants, tonicity adjusting agents, surfactants,flavorings, sweeteners or dyes, can be used.

In particular, auxiliaries and/or excipients of a type appropriate tothe desired formulation and the desired mode of administration are used.

The administration of the compounds, pharmaceutical compositions orcombinations according to the invention may be performed in any of thegenerally accepted modes of administration available in the art.Illustrative examples of suitable modes of administration includeintravenous, oral, nasal, parenteral, topical, transdermal and rectaldelivery. Oral and intravenous deliveries are preferred.

Generally, the pharmaceutical compositions according to the inventioncan be administered such that the dose of the active compound is in therange customary for Pi3K/Akt pathway inhibitors. In particular, a dosein the range of from 0.01 to 4000 mg of the active compound per day ispreferred for an average adult patient having a body weight of 70 kg. Inthis respect, it is to be noted that the dose is dependent, for example,on the specific compound used, the species treated, age, body weight,general health, sex and diet of the subject treated, mode and time ofadministration, rate of excretion, severity of the disease to be treatedand drug combination.

The pharmaceutical composition can be administered in a single dose perday or in multiple subdoses, for example, 2 to 4 doses per day. A singledose unit of the pharmaceutical composition can contain e.g. from 0.01mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1500mg, most preferably 1 to 500 mg, of the active compound. Furthermore,the pharmaceutical composition can be adapted to weekly, monthly or evenmore infrequent administration, for example by using an implant, e.g. asubcutaneous or intramuscular implant, by using the active compound inform of a sparingly soluble salt or by using the active compound coupledto a polymer.

The present invention further relates to comprising one or more firstactive ingredients selected from the compounds of the invention and oneor more second active ingredients selected from chemotherapeuticanti-cancer agents and target-specific anti-cancer agents e.g. fortreating, preventing or ameliorating diseases responsive or sensitive toinhibition of the Pi3K/Akt pathway, such as hyperproliferative diseasesof benign or malignant behaviour and/or disorders responsive to theinduction of apoptosis, particularly cancer, such as e.g. any of thosecancer diseases described above.

The invention further relates to the use of a pharmaceutical compositioncomprising one or more of the compounds according to this invention assole active ingredient(s) and a pharmaceutically acceptable carrier ordiluent in the manufacture of pharmaceutical products for the treatmentand/or prophylaxis of the illnesses mentioned above.

Depending upon the particular disease, to be treated or prevented,additional therapeutic active agents, which are normally administered totreat or prevent that disease, may optionally be coadministered with thecompounds according to this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease are known as appropriate for the disease beingtreated.

The anti-cancer agents mentioned herein above as combination partners ofthe compounds according to this invention are meant to includepharmaceutically acceptable derivatives thereof, such as e.g. theirpharmaceutically acceptable salts.

The person skilled in the art is aware of the total daily dosage(s) andadministration form(s) of the additional therapeutic agent(s)coadministered. Said total daily dosage(s) can vary within a wide rangedepending from the agent combined.

In practicing the present invention, the compounds according to hisinvention may be administered in combination therapy separately,sequentially, simultaneously, concurrently or chronologically staggered(such as e.g. as combined unit dosage forms, as separate unit dosageforms, as adjacent discrete unit dosage forms, as fixed or non-fixedcombinations, as kit-of-parts or as admixtures) with one or morestandard therapeutics (chemotherapeutic and/or target specificanti-cancer agents), in particular art-known anti-cancer agents, such asany of e.g. those mentioned above.

In this context, the present invention further relates to a combinationcomprising a first active ingredient, which is at least one compoundaccording to this invention, and a second active ingredient, which is atleast one art-known anti-cancer agent, such as e.g. one or more of thosementioned herein above, for separate, sequential, simultaneous,concurrent or chronologically staggered use in therapy, such as e.g. intherapy of any of those diseases mentioned herein.

The present invention further relates to a pharmaceutical compositioncomprising a first active ingredient, which is at least one compoundaccording to this invention, and a second active ingredient, which is atleast one art-known anti-cancer agent, such as e.g. one or more of thosementioned herein above, and, optionally, a pharmaceutically acceptablecarrier or diluent, for separate, sequential, simultaneous, concurrentor chronologically staggered use in therapy.

The present invention further relates to a combination productcomprising

a.) at least one compound according to this invention formulated with apharmaceutically acceptable carrier or diluent, andb.) at least one art-known anti-cancer agent, such as e.g. one or moreof those mentioned herein above, formulated with a pharmaceuticallyacceptable carrier or diluent.

The present invention further relates to a kit comprising a compound ofgeneral formula (I) according to claim 1.

The present invention further relates to a kit-of-parts comprising apreparation of a first active ingredient, which is a compound accordingto this invention, and a pharmaceutically acceptable carrier or diluent;a preparation of a second active ingredient, which is an art-knownanti-cancer agent, such as one of those mentioned above, and apharmaceutically acceptable carrier or diluent; for simultaneous,concurrent, sequential, separate or chronologically staggered use intherapy. Optionally, said kit comprises instructions for its use intherapy, e.g. to treat hyperproliferative diseases and diseasesresponsive or sensitive to inhibition of the Pi3K/Akt pathway, such ase.g. beningn or malignant neoplasia, particularly cancer, moreprecisely, any of those cancer diseases described above.

The present invention further relates to a combined preparationcomprising at least one compound according to this invention and atleast one art-known anti-cancer agent for simultaneous, concurrent,sequential or separate administration.

The present invention further relates to combinations, compositions,formulations, preparations or kits according to the present inventionhaving Pi3K/Akt pathway inhibitory activity.

In addition, the present invention further relates to a method fortreating in combination therapy hyperproliferative diseases and/ordisorders responsive to the induction of apoptosis, such as e.g. cancer,in a patient comprising administering a combination, composition,formulation, preparation or kit as described herein to said patient inneed thereof.

In addition, the present invention further relates to a method fortreating hyperproliferative diseases of benign or malignant behaviourand/or disorders responsive to the induction of apoptosis, such as e.g.cancer, in a patient comprising administering in combination therapyseparately, simultaneously, concurrently, sequentially orchronologically staggered a pharmaceutically active and therapeuticallyeffective and tolerable amount of a pharmaceutical composition, whichcomprises a compound according to this invention and a pharmaceuticallyacceptable carrier or diluent, and a pharmaceutically active andtherapeutically effective and tolerable amount of one or more art-knownanti-cancer agents, such as e.g. one or more of those mentioned herein,to said patient in need thereof.

In further addition, the present invention relates to a method fortreating, preventing or ameliorating hyperproliferative diseases and/ordisorders responsive to induction of apoptosis, such as e.g. benign ormalignant neoplasia, e.g. cancer, particularly any of those cancerdiseases mentioned herein, in a patient comprising administeringseparately, simultaneously, concurrently, sequentially orchronologically staggered to said patient in need thereof an amount of afirst active compound, which is a compound according to the presentinvention, and an amount of at least one second active compound, said atleast one second active compound being a standard therapeutic agent,particularly at least one art-known anti-cancer agent, such as e.g. oneor more of those chemotherapeutic and target-specific anti-cancer agentsmentioned herein, wherein the amounts of the first active compound andsaid second active compound result in a therapeutic effect.

In yet further addition, the present invention relates to a method fortreating, preventing or ameliorating, especially treatinghyperproliferative diseases and/or disorders responsive to induction ofapoptosis, such as e.g. benign or malignant neoplasia, especiallymalignanr neoplasia, e.g. cancer, particularly any of those cancerdiseases and tumor types mentioned herein, in a patient comprisingadministering a combination according to the present invention.

In addition, the present invention further relates to the use of acomposition, combination, formulation, preparation or kit according tothis invention in the manufacture of a pharmaceutical product, such ase.g. a commercial package or a medicament, for treating, preventing orameliorating, especially treating hyperproliferative diseases, and/ordisorders responsive to the induction of apoptosis, such as e.g.malignant or benign neoplasia, especially malignant neoplasia, such ase.g. cancer, particularly those diseases and tumor types mentionedherein.

The present invention further relates to a commercial package comprisingone or more compounds of the present invention together withinstructions for simultaneous, concurrent, sequential or separate usewith one or more chemotherapeutic and/or target specific anti-canceragents, such as e.g. any of those mentioned herein.

The present invention further relates to a commercial package consistingessentially of one or more compounds of the present invention as soleactive ingredient together with instructions for simultaneous,concurrent, sequential or separate use with one or more chemotherapeuticand/or target specific anti-cancer agents, such as e.g. any of thosementioned herein.

The present invention further relates to a commercial package comprisingone or more chemotherapeutic and/or target specific anti-cancer agents,such as e.g. any of those mentioned herein, together with instructionsfor simultaneous, concurrent, sequential or separate use with one ormore compounds according to the present invention.

The compositions, combinations, preparations, formulations, kits orpackages mentioned in the context of the combination therapy accordingto this invention may also include more than one of the compoundsaccording to this invention and/or more than one of the art-knownanti-cancer agents mentioned.

The first and second active ingredient of a combination or kit-of-partsaccording to this invention may be provided as separate formulations(i.e. independently of one another), which are subsequently broughttogether for simultaneous, concurrent, sequential, separate orchronologically staggered use in combination therapy; or packaged andpresented together as separate components of a combination pack forsimultaneous, concurrent, sequential, separate or chronologicallystaggered use in combination therapy.

The type of pharmaceutical formulation of the first and second activeingredient of a combination or kit-of-parts according to this inventioncan be according, i.e. both ingredients are formulated in separatetablets or capsules, or can be different, i.e. suited for differentadministration forms, such as e.g. one active ingredient is formulatedas tablet or capsule and the other is formulated for e.g. intravenousadministration.

The amounts of the first and second active ingredients of thecombinations, compositions or kits according to this invention maytogether comprise a therapeutically effective amount for the treatment,prophylaxis or amelioration of a hyperproliferative diseases and/or adisorder responsive to the induction of apoptosis, particularly one ofthose diseases mentioned herein, such as e.g. malignant or benignneoplasia, especially malignant neoplasia, e.g. cancer, like any ofthose cancer diseases and tumor types mentioned herein.

In addition, compounds according to the present invention can be used inthe pre- or post-surgical treatment of cancer.

In further addition, compounds of the present invention can be used incombination with radiation therapy.

As will be appreciated by persons skilled in the art, the invention isnot limited to the particular embodiments described herein, but coversall modifications of said embodiments that are within the spirit andscope of the invention as defined by the appended claims.

The following examples illustrate the invention in greater detail,without restricting it. Further compounds according to the invention, ofwhich the preparation is not explicitly, described, can be prepared inan analogous way.

The compounds, which are mentioned in the examples and the salts thereofrepresent preferred embodiments of the invention as well as a claimcovering all subcombinations of the residues of the compound of formula(I) as disclosed by the specific examples.

The term “according to” within the experimental section is used in thesense that the procedure referred to is to be used “analogously to”.

Experimental Part

The following table lists the abbreviations used in this paragraph andin the Intermediate Examples and Examples section as far as they are notexplained within the text body. NMR peak forms are stated as they appearin the spectra, possible higher order effects have not been considered.Chemical names were generated using AutoNom2000 as implemented in MDLISIS Draw. In some cases generally accepted names of commerciallyavailable reagents were used in place of AutoNom2000 generated names.

Abbreviation Meaning Boc t-Butoxycarbonyl Br broad Cl chemicalionisation D doublet Dd doublet of doublet DAD diode array detector DBU1,5-diazabicyclo(5.4.0)undec-5-ene DCM dichloromethane DIPdiisopropylether EtOAc ethyl acetate Eq. equivalent ESI electrospray(ES) ionisation HPLC high performance liquid chromatography LC-MS liquidchromatography mass spectrometry M multiplet MS mass spectrometry n-BuLin-Butyllithium NBS N-Bromo-Succinimide NMP N-methyl pyrrolidone NMRnuclear magnetic resonance spectroscopy: chemical shifts (δ) are givenin ppm. ONf nonafluorobutanesulfonate OTf trifluoromethanesulfonate OTstosylate Pd(dppf)Cl₂ 1,1′ bis(diphenylphosphino)ferrocene]dichloro-palladium(II) Pd(PtBu₃)₂ bis (tri-tert.-butylphosphin)palladium(0)[Pd(PtBu₃)₂], q quartet r.t. or rt room temperature RT retention time(as measured either with HPLC or UPLC) in minutes S singlet T tripletTHF tetrahydrofuran UPLC ultra performance liquid chromatography

Other abbreviations have their meanings customary per se to the skilledperson. The various aspects of the invention described in thisapplication are illustrated by the following examples which are notmeant to limit the invention in any way.

EXAMPLES UPLC-MS Standard Procedures

Analytical UPLC-MS was performed as described below. The masses (m/z)are reported from the positive mode electrospray ionisation unless thenegative mode is indicated (ES−).

In most of the cases method A is used. If not, it is indicated.

UPLC-MS Method A

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEHC18 1.7 50×2.1 mm, Eluent A: water+0.1% formic acid, Eluent B:acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate0.8 ml/min; Temperature: 60° C.; Injection: 2 μl; DAD scan: 210-400 nm.

UPLC-MS Method B

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEHC18 1.7 50×2.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile;Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Row rate 0.8 ml/min;Temperature: 60° C.; Injection: 2 μl: DAD scan: 210-400 nm; ELSD.

UPLC-MS Method C

Instrument: Waters Acquity UPLC-MS ZQ4000: Column: Acquity UPLC BEH C181.7 50×2.1 mm; Eluent A: water+0.05% formic acid Eluent B:acetonitrile+0.05% formic acid; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min99% B; Row rate 0.8 ml/min; Temperature: 60° C.; Injection: 2 μl; DADscan: 210-400 nm.

UPLC-MS Method D

Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH 0181.7 50×2.1 mm: Eluent A: water+0.2% ammonia, Eluent B: acetonitrile;Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 ml/min;Temperature: 6000; Injection: 2 μl; DAD scan: 210-400 nm; ELSD.

Intermediate Example Int-1-0

6-chloro-7-phenyl-imidazo[1,2-b]pyridazine Step 1:4-phenyl-1,2-dihydro-pyridazine-3,6-dione

46 g (264.1 mmol) 3-Phenyl-furan-2,5-dione were suspended in 1.56 Lwater. After addition of 34.4 g (264.1 mmol) hydrazine sulfate thereaction mixture was heated to reflux (bath temperature: 115° C.) andkept there for five hours. During the night the reaction mixture waskept at a bath temperature of 98° C. After cooling the precipitate wassucked off, washed with water (100 mL) and dried at 40° C. yielding 47.6g (95.8%) of the title compound.

Step 2: 3,6-dichloro-4-phenyl-pyridazine

47.5 g (252.4 mmol) 4-Phenyl-1,2-dihydro-pyridazine-3,6-dione weresuspended in 235 mL (2.52 mol) phosphorus oxychloride. The suspensionwas heated over night at 80° C. The reaction mixture was poured on 4.5 Lwater and stirred for 60′. The precipitate was sucked off, washed withwater (500 mL) and dried in a vacuum furnace at 40° C. yielding 56.8 gof the title compound which contains yet some water.

Step 3: 6-chloro-5-phenyl-pyridazin-3-yl-amine

36.5 g (162 mmol) 3,6-Dichloro-4-phenyl-pyridazine were suspended in1000 mL aqueous ammonia solution (25%) and stirred in an autoclave for18 hours at 100° C. The reaction mixture was transferred into aseparating funnel and the phases were separated. The aqueous phase waswashed twice with dichloromethane. The combined organic phases werewashed twice with water, the solvent was evaporated and the cruderesidue (two regioisomers, 6-chloro-5-phenyl-pyridazin-3-yl-amine and6-chloro-4-phenyl-pyridazin-3-yl-amine 20.2 g=60.6%) was used withoutfurther purification in the next step.

Step 4: 6-chloro-7-phenyl-imidazo[1,2-b]pyridazine

The mixture of 6-chloro-5-phenyl-pyridazin-3-yl-amine and6-chloro-4-phenyl-pyridazin-3-yl-amine (20.2 g=0.1 mol) was suspended in300 mL water and 30 mL THF. After addition of 32 mL (0.51 mol)chloracetaldehyde diethylacetal the reaction mixture was heated for fivehours at reflux. Additional 32 mL (0.51 mol) chloracetaldehydediethylacetal were added and heating was continued for another sixhours. The reaction mixture was diluted with ethyl acetate and extractedthree times. The organic phase was dried (sodium sulfate), filtrated andthe solvent was removed. The residue was purified by chromatography(Biotage, eluents: ethyl acetate/hexane). 6.8 g (30.1%) of the titlecompound, 6-chloro-7-phenyl-imidazo[1,2-b]pyridazine, and 6.4 g (28.4%)of the regioisomer, 6-chloro-8-phenyl-imidazo[1,2-b]pyridazine, wereobtained.

¹H-NMR (300 MHz, dDMSO): δ 8.38 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H),7.39-7.62 (m, 5H).

Intermediate Example Int-1-1

6-Chloro-2-methyl-7-phenyl-imidazo[1,2-b]pyridazine

The mixture of 6-chloro-5-phenyl-pyridazin-3-yl-amine and6-Chloro-4-phenyl-pyridazin-3-yl-amine (intermediate example Int-1-0,step 3, 65 g=316 mmol) in 65 mL tetrahydrofurane and 650 mL water washeated with 74.5 g (800 mmol) chloroacetone in analogy to the synthesisof the intermediate example Int-1-0, step 4, for 18 hours at reflux.After the usual work up and purification of the residue bychromatography (Biotage Isolera, Kronlab 8 cm, eluents:dichloromethane/methanol) and subsequent crystallization(methyl-tert.butylether/hexane) 11.69 g (30.4%) of the title compoundwere obtained.

¹H-NMR (300 MHz, CDCl₃): δ 8.10-8.16 (2H), 7.76 (1H), 7.50-7.59 (3H),7.14 (1H), 2.51 (s, 3H).

Intermediate Example Int-2-0

{1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester

100 mg (0.44 mmol) 6-Chloro-7-phenyl-imidazo[1,2-b]pyridazine(intermediate example Int-1-0) in 1.5 mL DME, 178.8 mg (0.48 mmol){1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, 0.85 mL aqueous sodium carbonate (10%) and 16 mg(0.02 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(II)were put in a microwave vial (no complete dissolution). The reactionmixture was degassed with argon, the vial closed with a cap and put in aheating block. The reaction mixture was stirred for 18 h at 90° C.(complete dissolution). Due to the still presence of starting materialadditional 86 mg boronic ester, 0.42 mL aqueous base and 8 mg palladiumcatalyst were added and stirring was continued for 6 hours at 90° C. 20mL water and 100 mL dichloromethane were added and the reaction mixturewas vigorously stirred for one hour. After separation of the organicphase the aqueous phase was extracted once more with dichloromethane.The combined organic extracts were washed with water and dried oversodium sulfate. After removal of the drying agent the solvent wasevaporated and the residue was purified by chromatography on silicagel(eluents: dichloromethane/methanol) yielding 109 mg (56.8%) of thedesired compound which was yet slightly contaminated.

MS (ES+, M+1): 441

¹H-NMR (400 MHz, CDCl₃): δ 8.03 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H),7.22-7.41 (m, 7H), 7.12-7.22 (m, 2H), 2.40-2.65 (m, 4H), 1.95-2.18 (m,1H), 1.72-1.93 (m, 1H), 1.12-1.53 (m, 9H).

Intermediate Example Int-2-1

{1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester

198 mg (0.45 mmol){1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester (intermediate example Int-2-0) and 80 mg (0.45mmol) N-bromosuccinimid were heated in 3.6 mL trichloromethane at refluxfor one hour. The solvent was evaporated and the residue was purified bychromatography on silicagel (eluents: dichloromethane/methanol) yielding115.6 mg (49.5%) of the desired bromo compound.

MS (ES+, M+1): 519/521

¹H-NMR (400 MHz, dDMSO): δ 8.18 (s, 1H), 7.98 (s, 1H), 7.15-7.35 (m,9H), 2.20-2.43 (m, 4H), 1.83-2.03 (m, 1H), 1.64-1.82 (m, 1H), 0.96-1.40(m, 9H).

Intermediate Example Int-2-2

{1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester

The title compound had been prepared by reacting6-chloro-2-methyl-7-phenyl-imidazo[1,2-b]pyridazine (intermediateexample Int-1-1) with{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester in analogy as described in intermediate exampleInt-2-0.

UPLC-MS: RT=1.51 min; m/z=455 (ES+, M+1)

Intermediate Example Int-2-3

{1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester

The title compound had been prepared by reacting{1-[4-(2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester (intermediate example Int-2-2) with NBS inchloroform in analogy as described in intermediate example Int-2-1.

UPLC-MS: RT=1.79 min; m/z=533/535 (ES+, M+1)

Intermediate Example Int-3-0

{1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester

101 mg (0.19 mmol){1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester (intermediate example Int-2-1) were dissolved in0.95 mL THF. After addition of 0.49 mL (0.97 mmol) of methylzincchloride (2M solution in THF) and 7.9 mg (0.01 mmol)bis(diphenylphosphino)ferrocenedichloropalladium(II) the reactionmixture was heated for 40′ in the microwave at 100° C. The reactionmixture was poured on water (30 mL) and extracted twice with ethylacetate (50 mL each). The combined organic extracts were washed withwater and dried over sodium sulfate. After filtration and evaporation ofthe solvent the residue was purified by chromatography on silicagel(eluents: dichloromethane/methanol) yielding 18.5 mg of the desiredcompound which was 90% pure.

MS (ES+, M+1): 455

¹H-NMR (300 MHz, CD₃OD): δ7.90 (s, 1H), 7.59 (s, 1H), 7.10-7.47 (m, 9H),2.62 (s, 3H), 2.29-2.55 (m, 4H), 1.95-2.18 (m, 1H), 1.73-1.95 (m, 1H),1.01-1.49 (m, 9H).

Intermediate Example Int-3-1

(1-{4-[3-(3-Cyanophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}cyclobutyl)-carbamicacid tert.-butyl ester

311 mg (0.6 mmol){1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-1, were dissolved in6.2 mL THF. After addition of 6 mL (3 mmol) of 3-(cyanophenyl)zinciodide (0.5M solution in THF) and 23 mg (0.03 mmol)bis(diphenylphosphino)ferrocenedichloropalladium(II) the reactionmixture was heated for 40′ in the microwave at 100° C. Additional 6 mL(3 mmol) of 3-(cyanophenyl)zinc iodide (0.5M solution in THF) and 46 mg(0.06 mmol) catalysator were added and the mixture was heated in themicrowave for an additional hour at 100° C. The reaction mixture waspoured on water (100 mL) and extracted twice with ethyl acetate (100 mLeach). The combined organic extracts were washed with water and driedover sodium sulfate. After filtration and evaporation of the solvent theresidue was purified by chromatography on silicagel (eluents:dichloromethane/methanol) yielding 121 mg of the desired compound whichhowever were strongly contaminated.

UPLC-MS: RT=1.53 min; m/z=543 (ES+, M+1)

Intermediate Example Int-3-2

(1-{4-[3-(4-Methanesulfonyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert.-butyl ester

170 mg (0.33 mmol){1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-1, 130.9 mg (0.66mmol) 4-(methanesulfonylphenyl)boronic acid, 26.7 mg (0.03 mmol) 1,1bis(diphenylphosphino)ferrocenedichloropalladium(II) and 104 mg (0.98mmol) sodium carbonate in 3.5 mL dioxane and 0.64 mL water were heatedin a microwave vial which had been sealed with a microwave cap for 18hours at 105° C. (heating block). The reaction mixture was poured onwater/dichloromethane and vigorously stirred for 30′. The organic phasewas separated, washed twice with brine, dried (sodium sulfate) andfiltrated. The solvent was evaporated and the crude residue (127.9 mg)was used in the next step without further purification.

The following intermediate examples had been prepared in analogyaccording to intermediate example Int-3-2 by reacting{1-[4-(3-bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-1, with theappropriate boronic acid.

Intermediate UPLC-MS example Structure/Name 1H-NMR resp. MS Int-3-3

  (1-{4-[3-(4-cyanophenyl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}cyclobutyl)-carbamic acid tert.- butyl ester (400 MHz, dDMSO): δ8.57 (s, 1H), 8.49 (d, 2H), 8.25 (s, 1H), 7.96 (d, 2H), 7.42 (d, 2H),7.21-7.38 (m, 7H), 2.28-2.40 (m, 2H), 2.04-2.15 (m, 2H), 1.92-2.04 (m,1H), 1.55-1.69 (m, 1H). Method B: RT = 1.52 min; m/z = 542 (ES+, M + 1)Int-3-4

  3-{6-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-benzoic acidmethyl ester Method B: RT = 1.54 min; m/z = 575 (ES+, M + 1) Int-3-5

  1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acidtert-butyl ester RT = 1.55 min; m/z = 535 (ES+, M + 1) Int-3-6

  {1-[4-(7-Phenyl-3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl esterMethod B: RT = 1.60 min; m/z = 531 (ES+, M + 1) Int-3-7

  (1-{4-[3-(3-Hydroxymethyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acidtert- butyl ester Method B: RT = 1.45 min; m/z = 547 (ES+, M + 1)Int-3-8

  (1-{4-[3-(4-Hydroxymethyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acidtert- butyl ester Method B: RT = 1.44 min; m/z = 547 (ES+, M + 1)Int-3-9

  (1-{4-[3-(4-Dimethylsulfamoyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acidtert- butyl ester Method B: RT = 1.54 min; m/z = 624 (ES+, M + 1)Int-3-10

  (1-{4-[7-Phenyl-3-(4-sulfamoyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acidtert-butyl ester RT = 1.39 min; m/z = 596 (ES+, M + 1) Int-3-11

  (1-{4-[3-(4-Fluoro-hydroxymethyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamicacid tert- butyl ester RT = 1.44 min; m/z = 565 (ES+, M + 1) Int-3-12

  (1-{4-[3-(4-Carbamoyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acidtert-butyl ester RT = 1.33 min; m/z = 560 (ES+, M + 1) Int-3-13

  (1-{4-[3-(3-Carbamoyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acidtert-butyl ester RT = 1.34 min; m/z = 560 (ES+, M + 1) Int-3-14

  4-{6-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl)-pyrazole-1-carboxylic acid tert-butyl ester RT = 1.56min; m/z = 607 (ES+, M + 1) Int-3-15

  (1-{4-[3-(6-Hydroxy-pyridin-3-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acidtert-butyl ester RT = 1.23 min; m/z = 534 (ES+, M + 1) Int-3-16

  5-{6-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridine-2-carboxylic acid methyl ester RT = 1.44 min;m/z = 576 (ES+, M + 1) Int-3-17

  5-{6-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyrazole-1-carboxylic acid tert-butyl ester RT = 1.32min; m/z = 507 (ES+, M + 1- Boc residue) Int-3-18

  (1-{4-[3-(1H-indazol-6-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acidtert-butyl ester UPLC-MS: RT = 1.41 min; m/z = 557 (ES+, M + 1) Int-3-19

  5-{6-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-nicotinicacid ethyl ester UPLC-MS: RT = 1.53 min; m/z = 590 (ES+, M + 1) Int-3-20

  (1-{4-[3-(5-Methoxypyridin-3-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acidtert-butyl ester UPLC-MS: RT = 1.44 min; m/z = 548 (ES+, M + 1)

Intermediate Example Int-4-0

(1-{4-[3-(3-Carbamoyl-phenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester

150 mg (0.28 mmol){1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-3, 92.8 mg (0.56mmol) 3-(carbamoylphenyl)boronic acid, 22.9 mg (0.028 mmol) 1,1bis(diphenylphosphino)ferrocenedichloropalladium(II) and 89.4 mg (0.84mmol) sodium carbonate in 3 mL dioxane and 0.4 mL water (both solventshad been degassed) were heated in the microwave for 30 minutes at 105°C. The reaction mixture was poured on water/dichloromethane/saturatedammonium chloride and vigorously stirred for 30′. The organic phase wasseparated, washed twice with brine, dried (sodium sulfate) andfiltrated. The solvent was evaporated and the crude residue (210mg>100%) was used without further purification in the next step.

UPLC-MS (method C): RT=1.39 min; m/z=574 (ES+, M+1)

The following intermediate examples had been prepared in analogyaccording to intermediate example Int-4-0 by reacting{1-[4-(3-bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-3, with theappropriate boronic acids.

Intermediate UPLC-MS resp. example Structure/Name 1H-NMR MS Int-4-1

  (1-{4-[3-(4-Fluoro-hydroxymethyl-phenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester RT = 1.59 min;m/z = 579 (ES+, M + 1) Int-4-2

  4-{6-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyrazole-1- carboxylic acid tert-butylester RT = 1.40 min; m/z = 521 (ES+, M + 1-Boc residue) Int-4-3

  1-{4-[3-(4-Fluorophenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acidtert- butyl ester RT = 1.72 min; m/z = 549 (ES+, M + 1) Int-4-4

  (1-{4-[3-(4-Carbamoyl-phenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acidtert- butyl ester RT = 1.44 min; m/z = 574 (ES+, M + 1) Int-4-5

  5-{6-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyrazole-1- carboxylic acid tert-butylester RT = 1.47 min; m/z = 521 (ES+, M + 1-Boc residue) Int-4-6

  5-{6-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-3-methyl- pyrazole-1-carboxylic acidtert-butyl ester RT = 1.74 min; m/z = 535 (ES+, M + 1-Boc residue)

Example 1

1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine

105 mg (0.24 mmol){1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, (intermediate example Int-2-0, slightlycontaminated), were stirred with 2.3 mL 4M hydrogen chloride in dioxanefor 10 days at room temperature. After evaporation of the solvent theresidue was brought to pH 9 with saturated aqueous sodium bicarbonatesolution. The mixture was stirred for four hours. The precipitate wassucked off and washed with water. The solid substance was dissolved indichloromethane and purified by chromatography on silicagel (eluents:dichloromethane/methanol) resulting in 49.6 mg of the desired compoundwhich was however yet contaminated. Due to these impurities the compoundwas again purified by HPLC yielding 21.1 mg (23.7%) of the titlecompound.

MS (ES+, M+1): 341

¹H-NMR (400 MHz, dDMSO): δ 8.32 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H),7.35 (d, 2H), 7.15-7.32 (m, 7H), 2.20-2.40 (m, 2H), 1.88-2.09 (m, 3H),1.53-1.69 (m, 1H).

Example 1.1

1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylaminehydrochloride

100 mg (0.22 mmol){1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, (intermediate example int-2-2), were stirredwith 7.5 mL 4M hydrogen chloride in dioxane over night at roomtemperature. After evaporation of the solvent the residue was treatedwith a mixture of methyl-tert. butylether and dichloromethane (1:1) andstirred over night at room temperature. The precipitate was filtered offyielding 132 mg (76%) of the title compound.

UPLC-MS: RT=0.83 min; m/z=338 (ES+, M-NH₂)

¹H-NMR (300 MHz, dDMSO): δ 8.80-9.05 (s, br., 3H), 8.38 (s, 1H),8.18-8.31 (m, 4H), 8.18 (s, 1H), 7.75 (d, 2H), 7.55-7.68 (m, 3H),2.54-2.70 (m, 4H), 2.48 (s, completely obscured by the signal of thesolvent, 3H), 2.10-2.30 (m, 1H), 1.72-1.90 (m, 1H).

Example 21-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine

18 mg (0.04 mmol){1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester (intermediate example Int-3-0) were dissolved in01 mL dioxane. 0.4 mL 4M hydrogen chloride in dioxane were added and themixture was stirred over night at room temperature. The solvent wasevaporated and the residue was treated with saturated sodium bicarbonatesolution. After stirring for one hour the reaction mixture was extractedthree times with ethyl acetate. The combined organic extracts werewashed with water and dried (sodium sulfate). After removal of thesolvent the residue was purified by chromatography on silicagel (eluentsdichloromethane/methanol) and additional HPLC yielding 2.3 mg (14%) ofthe title compound.

MS (ES+, M+1): 355

¹H-NMR (300 MHz, CD₃OD): δ 8.53 (br, NH₂, partly exchanged, 2H), 7.93(s, 1H), 7.62 (s, 1H), 7.38-7.52 (m, 4H), 7.12-7.38 (m, 5H), 2.55-2.75(m with a singulet within, 5H), 2.35-2.55 (m, 2H), 2.09-2.26 (m, 1H),1.79-1.98 (m, 1H).

Example 33-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile

115 mg (0.2 mmol)(1-{4-[3-(Cyanophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}cyclobutyl)-carbamicacid tert.-butyl ester, intermediate example Int-3-1, were stirred with10 mL 4M hydrogen chloride in dioxane for five days at room temperature.The solvent was evaporated and the residue was treated with saturatedsodium bicarbonate solution. After stirring for two hours the reactionmixture was extracted twice with dichloromethane. The combined organicextracts were washed with water and dried (sodium sulfate). Afterevaporating of the solvent the residue was purified by HPLC yielding 6.2mg of the title compound which is 90% pure.

UPLC-MS (method B): RT=1.34 min; m/z=442 (ES+, M+1)

¹H-NMR (300 MHz, CD₃OD): δ 8.67 (s, 1H), 8.49 (d, 1H), 8.32 (s, 1H),8.08 (s, 1H), 7.59-7.75 (m, 2H), 7.40-7.59 (m, 4H), 7.15-7.40 (m, 5H),2.58-2.80 (m, 2H), 2.33-2.58 (m, 2H), 2.10-2.29 (m, 1H), 1.80-2.29 (m,1H).

Example 41-{4-[3-(4-Methanesulfonylphenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine

120 mg (0.2 mmol)(1-{4-[3-(4-Methanesulfonyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert.-butyl ester, intermediate example Int-3-2, were stirred with10 mL 4M hydrogen chloride in dioxane for 23 hours at room temperature.The solvent was evaporated and the residue was treated with saturatedsodium bicarbonate solution (pH 9). After stirring for two hours 100 mLdichloromethane were added and stirring was continued for one hour. Theorganic phase was separated and the aqueous phase was extracted oncemore with dichloromethane (50 mL). The combined organic extracts werewashed with water, brine, dried, filtrated and the solvent wasevaporated. The crude product (97.8 mg) was purified by HPLC to yield20.8 mg of the title compound.

¹H-NMR (300 MHz, dDMSO): δ 8.52 (s, 1H), 8.50 (d, 2H), 8.29 (s, 1H),8.03 (d, 2H), 7.18-7.49 (m, 9H), 3.28 (s, 3H), 2.29-2.42 (m, partlyobscured by the signal of the solvent, 2H), 1.90-2.19 (m, 3H), 1.53-1.70(m, 1H).

The following examples had been prepared in analogy according to example4 by cleaving the protecting group in the corresponding intermediateexamples and subsequent purification or in the case of thehydrochlorides by filtering the title compounds off as described inexample 1.1.

UPLC-MS Example Structure/Name 1H-NMR resp. MS 4.1

  4-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile (400 MHz, dDMSO): δ 8.57 (s, 1H), 8.49(d, 2H), 8.25 (s, 1H), 7.96 (d, 2H), 7.42 (d, 2H), 7.21-7.38 (m, 7H),2.28- 2.40 (m, 2H), 2.04-2.15 (m, 2H), 1.92-2.04 (m, 1H), 1.55-1.69 (m,1H). (ES+, M − NH₂): 425 4.2

  3-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzoic acid methyl ester ¹H-NMR (300 MHz, dDMSO): δ9.03 (s, 1H), 8.38-8.51 (m, 2H), 8.21 (s, 1H), 7.93 (d, 1H), 7.67 (dd,1H), 7.15-7.48 (m, 9H), 3.89 (s, 3H), 2.25-2.39 (m, 2H), 1.89- 2.10 (m,3H), 1.52-1.68 (m, 1H). RT = 1.00 min; m/z = 458 (ES+, M − NH₂) 4.3

  1-{4-[3-(4-Fluorophenyl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine ¹H-NMR (300 MHz, dDMSO): δ 8.31 (s, 1H),8.15-8.30 (m, 4H), 7.19- 7.48 (m, 10H), 2.31-2.48 (m, partly obscured bythe signal of the solvent, 2H), 2.10-2.30 (m, 2H), 1.92-2.12 (m, 1H),1.58- 1.76 (m, 1H). RT = 0.99 min; m/z = 418 (ES+, M − NH₂) 4.4

  1-[4-(7-Phenyl-3-p-tolyl- imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine RT = 1.02 min; m/z = 431 (ES+, M + 1) 4.5

  (3-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol Method B: RT = 1.23 min; m/z = 430(ES+, M − NH₂) 4.6

  (4-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol formiate (400 MHz, dDMSO): δ 8.30 (s,1H), 8.21 (s, 1H), 8.19 (s, 1H), 8.17 (d, 2H), 7.38-7.48 (m, 4H),7.19-7.38 (m, 7H), 4.52 (s, 2H), 2.32-2.42 (m, 2H), 2.09-2.20 (m, 2H),1.92-2.05 (m, 1H), 1.59- 1.72 (m, 1H). Method B: RT = 1.11 min; m/z =447 (ES+, M + 1) 4.7

  4-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}- benzenesulfonamide hydrocloride (400 MHz, dDMSO): δ8.75-8.92 (s, br., 3H), 8.64 (s, 1H), 8.32-8.40 (m, 3H), 7.96 (d, 2H),7.25-7.59 (m, 11H), 2.48- 2.59 (m, 4H), 2.10-2.22 (m, 1H), 1.69-1.82 (m,1H). RT = 0.83 min; m/z = 479 (ES+, M − NH₂) 4.8

  1-[4-(3-Bromo-7-phenyl- imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine hydrochloride (300 MHz, dDMSO): δ 8.69-8.89 (s,br., 3H), 8.21 (s, 1H), 8.05 (s, 1H), 7.50 (d, 2H), 7.39 (d, 2H),7.20-7.38 (m, 5H), 2.48-2.59 (m, 4H), 2.10- 2.22 (m, 1H), 1.69-1.82 (m,1H). RT = 0.92 min; m/z = 402/404 (ES+, M − NH₂) 4.9

  (5-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)- methanol hydrochloride (400 MHz,dDMSO): δ 8.72-8.92 (s, br., 3H), 8.54 (s, 1H), 8.38 (s, 1H), 8.28-8.34(m, 1H), 8.08- 8.15 (m, 1H), 7.42-7.58 (m, 4H), 7.25-7.42 (m, 6H), 4.63(s, 2H), 2.49- 2.60 (m, partly obscured by the signal of the solvent,4H), 2.09-2.22 (m, 1H), 1.69-1.83 (m, 1H). Method C: RT = 0.83 min; m/z= 448 (ES+, M − NH₂) 4.10

  4-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide hydrochloride (300 MHz, dDMSO): δ 8.72-8.89(s, br., 3H), 8.60 (s, 1H), 8.35 (s, 1H), 8.30 (d, 2H), 8.01 (d, 2H),7.26-7.59 (m, 11H), 2.49-2.61 (m, partly obscured by the signal of thesolvent, 4H), 2.05- 2.28 (m, 1H), 1.68-1.85 (m, 1H). RT = 0.81 min; m/z= 443 (ES+, M − NH₂) 4.11

  3-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide hydrochloride (400 MHz, dDMSO): δ 8.78-8.90(s, br., 3H), 8.69 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 8.35 (d, 1H),8.15 (s, 1H), 7.92 (d, 1H), 7.62 (dd, 1H), 7.42-7.58 (m, 5H), 7.25- 7.42(m, 5H), 2.49-2.61 (m, partly obscured by the signal of the solvent,4H), 2.10-2.22 (m, 1H), 1.68-1.82 (m, 1H). RT = 0.82 min; m/z = 443(ES+, M − NH₂) 4.12

  1-{4-[7-Phenyl-3-(1H-pyrazol-4-yl)- imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine (400 MHz, dDMSO): δ 8.35 (s, 2H), 8.25 (s, 1H),8.16 (s, 1H), 8.13 (s, 1H), 7.38-7.48 (m, 4H), 7.20- 7.38 (m, 5H),2.35-2.48 (m, partly obscurd by the signal of the solvent, 2H),2.18-2.30 (m, 2H), 1.98- 2.10 (m, 1H), 1.62-1.75 (m, 1H). RT = 0.77 min;m/z = 390 (ES+, M − NH₂) 4.13

  5-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridin-2-ol (400 MHz, dDMSO): δ 8.43 (d, 1H), 8.22(s, 1H), 8.19 (s, 1H), 8.11 (d, 1H), 7.15-7.45 (m, 10H), 6.51 (d, 1H),2.25- 2.40 (m, 2H), 1.90-2.13 (m, 3H), 1.53-1.69 (m, 1H). RT = 0.76 min;m/z = 417 (ES+, M − NH₂) 4.14

  5-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridine-2- carboxylic acid methyl ester (400 MHz,CDCl₃): δ 9.68 (d, 1H), 8.68 (d, 1H), 8.31 (s, 1H), 8.29 (d, 1H), 8.09(s, 1H), 7.17- 7.48 (m, 9H), 4.09 (s, 3H), 2.49-2.61 (m, 2H), 2.00-2.28(m, 3H), 1.72- 1.90 (m, partly obscured by the water signal of thesolvent, 1H). RT = 0.91 min; m/z = 459 (ES+, M − NH₂) 4.15

  1-{4-[7-Phenyl-3-(2H-pyrazol-3-yl)- imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine (400 MHz, CD₃OD): δ 8.23 (s, 1H), 8.08 (s, 1H),7.67-7.88 (m, 1H), 7.18- 7.52 (m, 10H), 2.52-2.69 (m, 2H), 2.25-2.40 (m,2H), 2.05-2.20 (m, 1H), 1.72-1.90 (m, 1H). RT = 0.83 min; m/z = 407(ES+, M + 1) 4.16

  1-{4-[3-(1H-indazol-6-yl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine (400 MHz, CD₃OD): δ 8.64 (s, 1H), 8.29 (s, 1H),8.01-8.10 (m, 2H), 7.80- 7.90 (m, 2H), 7.40-7.55 (m, 4H), 7.20-7.39 (m,5H), 2.59-2.72 (m, 2H), 2.38-2.51 (m, 2H), 2.09- 2.22 (m, 1H), 1.80-1.93(m, 1H). RT = 0.89 min; m/z = 460 (ES+, M − NH₂) 4.17

  5-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-nicotinic acid ethyl ester (300 MHz, CD₃OD): δ 9.52(d, 1H), 9.32 (d, 1H), 9.05 (d, 1H), 8.39 (s, 1H), 8.07 (s, 1H),7.38-7.50 (m, 4H), 7.20- 7.38 (m, 5H), 4.43 (q, 2H), 2.45-2.62 (m, 2H),2.19-2.32 (m, 2H), 1.99- 2.18 (m, 1H), 1.68-1.82 (m, 1H), 1.41 (t, 3H).RT = 0.90 min; m/z = 490 (ES+, M + 1) 4.18

  1-{4-[3-(5-Methoxypyridin-3-yl)-7- phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine (300 MHz, CD₃OD): δ 8.99 (d, 1H), 8.39 (s,1H), 8.33 (d, 1H), 8.21 (d, 1H), 8.08 (s, 1H), 7.39-7.51 (m, 4H), 7.22-7.39 (m, 5H), 3.95 (s, 3H), 2.50-2.66 (m, 2H), 2.25-2.41 (m, 2H), 2.01-2.22 (m, 1H), 1.70-1.90 (m, 1H). RT = 0.83 min; m/z = 448 (ES+, M + 1)

Example 5

3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide

210 mg Crude(1-{4-[3-(3-carbamoyl-phenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester, intermediate example Int-4-0, were stirred with15 mL 4M hydrogen chloride in dioxane over night at room temperature.The solvent was evaporated and the residue was dissolved inmethanol/dichloromethane. Methyl-tert.butylether was added until theproduct precipitated. The reaction mixture was stirred for one hour andthe precipitate was sucked off. The crystals were dissolved in methanoland given on a ForaPak Rxn CX column. The column was washed with 100 mLmethanol and the product was eluted with methanol/NH₃. After evaporationof the solvents the residue was purified by HPLC to yield 39.3 mg of thetitle compound.

¹H-NMR (400 MHz, dDMSO): δ 8.38-8.48 (m, 3H), 8.15 (d, 2H), 8.08 (s,1H), 8.01 (s, 1H), 7.91-7.99 (m, 2H), 7.51-7.69 (m, 6H), 7.42 (s, 1H),2.59 (s, 3H), 2.40-2.52 (m, obscured by the signal of the solvent, 2H),2.21-2.32 (m, 2H), 1.98-2.11 (m, 1H), 1.83-1.78 (m, 1H).

The following examples had been prepared in analogy according to example5 by cleaving the protecting group in the corresponding intermediateexamples and subsequent purification,

UPLC-MS resp. Example Structure/Name 1H-NMR MS 5.1

  (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2- methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)- methanol (300 MHz, dDMSO): δ 8.42 (d,2H), 8.18 (d, 2H), 7.91- 8.03 (m, 2H), 7.68-7.80 (m, 1H), 7.49-7.68 (m,5H), 7.28- 7.42 (m, 1H), 4.66 (s, 2H), 2.57 (s, 3H), 2.38-2.60 (m,completely obscured by the signal of the solvent, 2H), 2.19-2.35 (m,2H), 1.92- 2.13 (m, 1H), 1.60-1.80 (m, 1H). RT = 1.03 min; m/z = 523(ES−, M − 1) 5.2

  1-{4-[2-Methyl-7-phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine (400 MHz,CD₃OD): δ 8.35 (2H), 8.01-8.15 (m, 4H), 7.68 (s, 1H), 7.60 (d, 2H),7.50-7.59 (m, 3H), 2.60-2.72 (m, 2H), 2.62 (s, 3H), 2.33- 2.48 (m, 2H),2.09-2.22 (m, 1H), 1.79-1.92 (m, 1H). RT = 0.88 min; m/z = 404 (ES+, M −NH₂) 5.3

  1-{4-[3-(4-Fluorophenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine RT = 1.11min; m/z = 493 (ES−, M − 1) 5.4

  4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2- methyl-7-phenyl-imidazol[1,2-b]pyridazin-3-yl}-benzamide (400 MHz, dDMSO): δ 8.38- 8.45 (m, 2H),8.01-8.12 (m, 5H), 8.00 (s, 1H), 7.93 (d, 2H), 7.50-7.65 (m, 5H), 7.41(s, br., 1H), 2.59 (s, 3H), 2.38-2.45 (m, slightly obscured by thesignal of the solvent, 2H), 2.10-2.21 (m, 2H), 1.92-2.05 (m, 1H), 1.59-1.72 (m, 1H). RT = 0.89 min; m/z = 518 (ES−, M − 1) 5.5

  1-{4-[2-Methyl-7-phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine (400 MHz,CD₃OD): δ 8.08- 8.13 (m, 4H), 7.82 (d, 1H), 7.78 (s, 1H), 7.50-7.65 (m,5H), 7.13 (br., 1H), 2.70 (s, 3H), 2.55-2.68 (m, 2H), 2.25- 2.39 (m,2H), 2.05-2.19 (m, 1H), 1.72-1.88 (m, 1H). RT = 0.85 min; m/z = 338(ES+, M − NH₂-pyrazol) 5.6

  1-{4-[2-Methyl-7-phenyl-3-(5-methyl-2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6- yl]-phenyl}-cyclobutylamine(300 MHz, CD₃OD): δ 8.02- 8.20 (m, 4H), 7.79 (s, 1H), 7.49-7.69 (m, 5H),6.85 (br., 1H), 2.57-2.72 (m, 5H), 2.42 (s, 3H), 2.29-2.41 (m, 2H),2.05-2.22 (m, 1H), 1.74-1.92 (m, 1H). RT = 0.89 min; m/z = 338 (ES+, M −NH₂- methylpyrazol)

Example 61-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamineStep 1:(1-{4-[2-bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester

100 mg (0.19 mmol)1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester, intermediate example Int-3-5, and 49.9 mg (0.28mmol) N-bromosuccinimide in 1.5 mL trichloromethane were heated atreflux over night. The solvent was evaporated and the residue dissolvedin dichloromethane. The organic phase was extracted trice with saturatedsodium hydrogencarbonate, with water and brine and dried (sodiumsulfate). After evaporation of the solvent the residue was purified bychromatography on silicagel yielding 36 mg (31.4%) of the titlecompound.

¹H-NMR (300 MHz, dDMSO): δ 8.18 (s, 1H), 7.82-7.96 (m, 2H), 7.54 (br.,1H), 7.32-7.48 (m, 2H), 7.12-7.32 (m, 9H), 2.19-2.40 (m, 4H), 1.82-2.00(m, 1H), 1.60-1.80 (m, 1H), 0.98-1.38 (m, 9H).

Step 2:1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine

36 mg (0.06 mmol)(1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester in 2.7 mL 4M hydrogen chloride in dioxane werestirred over night at room temperature. After evaporation of the solventthe residue was dissolved in methanol and given on a ForaPak Rxn CXcolumn. The column was washed with 100 mL methanol and the product waseluted with methanol/NH₃ yielding 29 mg (91.5%) of the title compound.

¹H-NMR (400 MHz, dDMSO): δ 8.19 (s, 1H), 7.85-7.95 (m, 2H), 7.15-7.45(m, 11H), 2.26-2.40 (m, 2H), 2.03-2.18 (m, 2H), 1.89-2.03 (m, 1H),1.55-1.69 (m, 1H).

Example 7

1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamineStep 1:(1-{4-[2-chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester

100 mg (0.19 mmol)1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester, intermediate example Int-3-5, and 37.5 mg (0.28mmol) N-chlorosuccinimide in 1.5 mL trichloromethane were boiled overnight. The solvent was evaporated and the residue dissolved indichloromethane. The organic phase was extracted trice with saturatedsodium hydrogencarbonate, with water and brine and dried (sodiumsulfate). The solvent was evaporated and the residue was purified bychromatography on silicagel yielding 12.1 mg (11.4%) of the titlecompound.

¹H-NMR (300 MHz, dDMSO): δ 8.19 (s, 1H), 7.86-8.01 (m, 2H), 7.58 (br.,1H), 7.33-7.49 (m, 2H), 7.12-7.32 (m, 9H), 2.18-2.40 (m, 4H), 1.82-2.01(m, 1H), 1.60-1.80 (m, 1H), 0.94-1.40 (m, 9H).

Step 2:1-{4-[2-chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine

12.1 mg (0.98 mmol)(1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester in 1 mL 4M hydrogen chloride in dioxane werestirred over night at room temperature. After evaporation of the solventthe residue was dissolved in methanol and given on a ForaPak Rxn CXcolumn. The column was washed with 100 mL methanol and the product waseluted with methanol/NH₃ yielding 9.8 mg (93.4%) of the title compound.

¹H-NMR (300 MHz, dDMSO): δ 8.19 (s, 1H), 7.88-8.01 (m, 2H), 7.13-7.49(m, 11H), 2.35-2.50 (m, partly obscured by the signal of the solvent,2H), 2.19-2.29 (m, 2H), 1.90-2.11 (m, 1H), 1.58-1.78 (m, 1H).

Example 8(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamideStep 1:(1-{4-[3-((E)-2-carbamoyl-vinyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester 133 mg (0.256 mmol){1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-1, 36.4 mg

(0.5 mmol) acrylamide, 13.3 mg (0.04 mmol) tri-2-tolylphosphane, 5.8 mg(0.026 mmol) palladium(II)acetate and 0.041 mL (0.292 mmol)triethylamine in 1.8 mL degassed acetonitrile were heated in themicrowave at 110° C. for one hour. The reaction mixture was poured onwater/saturated ammonium chloride/dichloromethane and vigorously stirredfor 30 minutes. The organic phase was separated; washed with brine,dried, and the solvent was removed. The crude product (162 mg>100%) wasused in the next step without further purification.

UPLC-MS: RT=1.26 min; m/z=510 (ES+, M+1)

Step 2:(E)-3-{6-[4-(1-amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide

162 mg Crude(1-{4-[3-((E)-2-carbamoyl-vinyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester were stirred in 10.2 mL 4M hydrogen chloride indioxane for 16 hours at room temperature. After evaporation of thesolvent the residue was dissolved in methanol and given on a PoraPak RxnCX column. The column was washed with 100 mL methanol and the productwas eluted with methanol/NH₃ yielding 34 mg (13%) of the title compoundwhich was however strongly contaminated.

UPLC-MS: RT=0.76 min; m/z=393 (ES+, M-NH₂)

Example 9

1-[4-(7-Phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamineStep 1:{1-[4-(7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamicacid tert-butyl ester

133 mg (0.256 mmol){1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-1, 61.6 mg (0.256mmol) 2,4,6-trivinyl-cyclotriboroxane, 29.6 mg (0.026 mmol) tetrakistriphenylphosphine palladium(0) and 35.4 mg (0.256 mmol) potassiumcarbonate in 2 mL dimethoxyethane and 0.7 mL water were heated in amicrowave vial (heating block) at 110° C. for 16 hours. The reactionmixture was poured on water/saturated ammonium chloride/dichloromethaneand vigorously stirred for 30 minutes. The organic phase was separated,washed with brine, dried, and the solvent was removed. The crude product(168 mg>100%) was used in the next step without further purification.

UPLC-MS: RT=1.51 min; m/z=467 (ES+, M+1)

Step 2:1-[4-(7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine

168 mg Of the crude{1-[4-(7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamicacid tert-butyl ester were stirred in 11.5 mL 4M hydrogen chloride indioxane for 16 hours at room temperature. After evaporation of thesolvent the residue was dissolved in methanol and given on a PoraPak RxnCX column. The column was washed with 100 mL methanol and the productwas eluted with methanol/NH₃ yielding 34 mg (21.6%) of the titlecompound which was however slightly contaminated.

UPLC-MS: RT=0.82 min; m/z=411 (ES−, M−1)

Example 10

(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamideStep 1:(1-{4-[3-((E)-2-carbamoyl-vinyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester

200 mg (0.375 mmol){1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, (intermediate example Int-2-3), 53.3 mg (0.75mmol) acrylamide, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg(0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol)triethylamine in 2.6 mL degassed acetonitrile were heated in themicrowave at 110° C. for three hours. The reaction mixture was poured onwater/saturated ammonium chloride/dichloromethane and vigorously stirredfor 30 minutes. The organic phase was separated, washed with brine,dried, and the solvent was removed. The crude product (247 mg) was usedin the next step without further purification.

UPLC-MS: RT=1.40 min; m/z=524 (ES+, M+1)

Step 2:(E)-3-{6-[4-(1-amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide

247 mg Of the crude(1-{4-[3-((E)-2-carbamoyl-vinyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamicacid tert-butyl ester were stirred in 15 mL 4M hydrogen chloride indioxane for 22 hours at room temperature. The solvent was evaporated andthe residue was treated with saturated sodium bicarbonate solution (pH9). After stirring for one hour 100 mL dichloromethane were added andstirring was continued for one hour. The organic phase was separated andthe aqueous phase was extracted once more with dichloromethane (50 mL).The combined organic extracts were washed with water and brine, dried,filtrated and the solvent was evaporated. The crude product (197.2 mg)was purified by HPLC to yield 50.3 mg of the title compound which washowever contaminated.

¹H-NMR (300 MHz, CD₃OD): δ 818 (d, 2H), 8.02-8.12 (m, 2H), 8.01 (d, 1H),7.82 (s, 1H), 7.65 (d, 2H), 7.48-7.62 (m, 3H), 7.23 (d, 1H), 2.52-2.73(m, 5H), 2.29-2.49 (m, 2H), 2.03-2.22 (m, 1H), 1.75-1.93 (m, 1H).

Example 11

(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylicacid methyl ester Step 1:(E)-3-{6-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylicacid methyl ester

200 mg (0.375 mmol){1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-3, 64.5 mg (0.75mmol) methyl acrylate, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol)triethylamine in 2.6 mL degassed acetonitrile were heated in themicrowave at 110° C. for three hours. Due to an incomplete reactionadditional 32.2 mg (0.375 mmol) methyl acrylate and 8.5 mg (0.037 mmol)palladium(II) acetate were added, and heating in the microwave wascontinued for three hours. The reaction mixture was poured onwater/saturated ammonium chloride/dichloromethane and vigorously stirredfor 30 minutes. The organic phase was separated, washed twice withbrine, dried, and the solvent was removed. The crude product (300 mg)was used in the next step without further purification.

UPLC-MS: RT=1.67 min; m/z=539 (ES+, M+1)

Step 2:(E)-3-{6-[4-(1-amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylicacid methyl ester

299 mg Of the crude(E)-3-{6-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylicacid methyl ester were stirred in 17.6 mL 4M hydrogen chloride indioxane for 22 hours at room temperature. The solvent was evaporated andthe residue was treated with saturated sodium bicarbonate solution (pH9). After stirring for one hour 100 mL dichloromethane were added andstirring was continued for one hour. The organic phase was separated andthe aqueous phase was extracted once more with dichloromethane (50 mL).The combined organic extracts were washed with water and brine, dried,filtrated and the solvent was evaporated. The crude product (236 mg) waspurified by HPLC to yield 40 mg of the title compound.

¹H-NMR (400 MHz, CD₃OD): δ 8.03-8.12 (m, 4H), 7.92 (d, 1H), 7.81 (s,1H), 7.50-7.65 (m, 5H), 7.18 (d, 1H), 3.82 (s, 3H), 2.58-2.69 (m, 2H),2.56 (s, 3H), 2.26-2.40 (m, 2H), 2.08-2.21 (m, 1H), 1.75-1.90 (m, 1H).

Example 12

1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamineStep 1:{1-[4-(2-methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamicacid tert-butyl ester

200 mg (0.375 mmol){1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamicacid tert.-butyl ester, intermediate example Int-2-3, 90.3 mg (0.375mmol) 2,4,6-trivinyl-cyclotriboroxane, 43 mg (0.038 mmol) tetrakistriphenylphosphine palladium(0) and 51.8 mg (0.375 mmol) potassiumcarbonate in 2.9 mL dimethoxyethane and 1 mL water were heated in amicrowave vial at 110° C. for 16 hours. The reaction mixture was pouredon water/saturated ammonium chloride/dichloromethane and vigorouslystirred for 30 minutes. The organic phase was separated and the aqueousphase extracted once more with dichloromethane. The combined organicextracts were washed twice with brine, dried, and the solvent wasremoved. The crude product (244 mg) was used in the next step withoutfurther purification.

UPLC-MS: RT=1.70 min; m/z=481 (ES+, M+1)

Step 2:1-[4-(2-methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine

244 mg Of the crude{1-[4-(2-methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamicacid tert-butyl ester were stirred in 16.1 mL 4M hydrogen chloride indioxane for 22 hours at room temperature. The reaction mixture wasworked up as described in the previous example. The crude product (178mg) was purified by HPLC to yield 35.3 mg of the title compound.

¹H-NMR (300 MHz, CD₃OD): δ 8.01-8.19 (m, 4H), 7.75 (s, 1H), 7.49-7.68(m, 5H), 7.07-7.21 (m, 1H), 6.40 (d, 1H), 5.57 (d, 1H), 2.51-2.70 (m,5H), 2.25-2.40 (m, 2H), 2.03-2.20 (m, 1H), 1.72-1.90 (m, 1H).

Example 13

1-[4-(3-Ethyl-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine

14.3 mg (0.04 mmol)1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,example 12, were given in five mL ethyl acetate (no completedissolution). After addition of a catalytic amount of palladium/charcoal(10%) the reaction mixture was stirred under a hydrogen atmosphere forthree hours. Due to an incomplete reaction one mL ethanol was added andstirring was continued over night. The catalyst was sucked off via aglass fibre filter and washed with ethanol. After evaporation of thesolvents 11.9 mg (66.2%) of the title compound were obtained which wereslightly contaminated.

¹H-NMR (300 MHz, CD₃OD): δ 8.15 (d, 2H), 7.99-8.12 (m, 2H), 7.69 (s,1H), 7.65 (d, 2H), 7.42-7.60 (m, 3H), 3.13 (q, 2H), 2.60-2.75 (m, 2H),2.33-2.52 (m, 5H), 2.08-2.26 (m, 1H), 1.80-1.95 (m, 1H), 1.34 (t, 3H).

Biological Investigations

The following assays can be used to illustrate the commercial utility ofthe compounds according to the present invention.

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

Biological Assay 1.0 Akt1 Kinase Assay

Akt1 inhibitory activity of compounds of the present invention wasquantified employing the Akt1 TR-FRET assay as described in thefollowing paragraphs. His-tagged human recombinant kinase full-lengthAkt1 expressed in insect cells was purchased form Invitrogen (partnumber PV 3599). As substrate for the kinase reaction the biotinylatedpeptide biotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was usedwhich can be purchased e.g. from the company Biosynthan GmbH(Berlin-Buch, Germany).

For the assay 50 nl of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of asolution of Akt1 in assay buffer [50 mM TRIS/HCl pH 7.5, 5 mM MgCl₂, 1mM dithiothreitol, 0.02% (v/v) Triton X-100 (Sigma)] were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.Then the kinase reaction was started by the addition of 3 μl of asolution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5μl assay volume is 10 μM) and substrate (1.67 μM=>final conc. in the 5μl assay volume is 1 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 60 min at 22° C. The concentration ofAkt1 in the assay was adjusted depending of the activity of the enzymelot and was chosen appropriate to have the assay in the linear range,typical enzyme concentrations were in the range of about 0.05 ng/μl(final conc. in the 5 μl assay volume).

The reaction was stopped by the addition of 5 μl of a solution of HTRFdetection reagents (200 nM streptavidine-XL665 [Cisbio] and 1.5 nManti-phosho-Serine antibody [Millipore, cat. #35-001] and 0.75 nM LANCEEu-W 1024 labeled anti-mouse IgG antibody [Perkin Elmer]) in an aqueousEDTA-solution (100 mM EDTA, 0.1% (w/v) bovine serum albumin in 50 mMHEPES/NaOH pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the antibodies. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theanti-mouse-IgG-Eu-Chelate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100 fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit using an inhouse software.

Biological Assay 2.0 Akt2 Kinase Assay

Akt2 inhibitory activity of compounds of the present invention wasquantified employing the Akt2 TR-FRET assay as described in thefollowing paragraphs.

His-tagged human recombinant kinase full-length Akt2 expressed in insectcells and activated by PDK1 was purchased form Invitrogen (part numberPV 3975). As substrate for the kinase reaction the biotinylated peptidebiotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used which canbe purchased e.g. from the company Biosynthan GmbH (Berlin-Buch,Germany).

For the assay 50 nl of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of asolution of Akt2 in assay buffer [50 mM TRIS/HCl pH 7.5, 5 mM MgCl₂, 1mM dithiothreitol, 0.02% (v/v) Triton X-100 (Sigma)] were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.Then the kinase reaction was started by the addition of 3 μl of asolution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5μl assay volume is 10 μM) and substrate (1.67 μM=>final conc. in the 5μl assay volume is 1 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 60 min at 22° C. The concentration ofAkt2 in the assay was adjusted depending of the activity of the enzymelot and was chosen appropriate to have the assay in the linear range,typical enzyme concentrations were in the range of about 0.2 ng/μl(final conc. in the 5 μl assay volume).

The reaction was stopped by the addition of 5 μl of a solution of HTRFdetection reagents (200 nM streptavidine-XL665 [Cisbio] and 1.5 nManti-phosho-Serine antibody [Millipore, cat. #35-001] and 0.75 nM LANCEEu-W 1024 labeled anti-mouse IgG antibody [Perkin Elmer]) in an aqueousEDTA-solution (100 mM EDTA, 0.1%/w/v\ bovine serum albumin in 50 mMHEPES/NaOH pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the antibodies. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theanti-mouse-IgG-Eu-Chelate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100 fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit using an inhouse software.

Preferred compounds of the present invention show in either the Akt1 orAkt2 kinase assay: median IC₅₀<5 μM, more preferably, median IC₅₀<0.5μM, even more preferably, median IC₅₀≦0.1 μM.

The following Table gives selected data for selected Examples of thepresent invention.

Akt1, median Akt2, median Example IC₅₀, μM IC₅₀, μM 1-0 0.246 1.439 1-117.257 20.000 2-0 0.441 1.726 3-0 0.005 0.082 4-0 0.110 0.278 4-1 0.1290.136 4-2 0.004 0.058 4-3 0.036 0.081 4-4 0.044 0.277 4-5 0.006 0.0374-6 0.019 0.123 4-7 0.047 0.151 4-8 0.074 0.264 4-9 0.009 0.092  4-100.027 0.118  4-11 0.013 0.068  4-12 0.009 0.067  4-13 0.146 0.431  4-140.019 0.115  4-15 0.011 0.070  4-16 0.011 0.022  4-17 0.007 0.110  4-180.005 0.046 5-0 15.038 16.764 5-1 10.115 16.725 5-2 4.780 not tested 5-34.428 5.107 5-4 12.083 4.823 5-5 2.732 5.228 5-6 14.853 17.150 6-0 0.0680.041 7-0 0.099 0.106 8-0 0.038 0.222 9-0 0.044 0.326 10-0  18.03120.000 11-0  5.966 10.120 12-0  8.937 16.689 13-0  20.000 20.000

Cellular Assays 3.0 p-AKT1/2/3-S473, -T308, and p-4E-BP1-T70 assays

The molecular mechanism of action was investigated in a set ofexperiments to assess the inhibition of the PI3K-AKT-mTOR pathway inresponsive cell lines such as KPL4 breast tumour cell line(PIK3CAH1047R, HER2O/E and hormone independent). The phospho-substratesof PI3K-AKT-mTOR axis were used as the read-outs to reflect pathwayinhibition. Cells were seeded at 60-80% confluency per well in 96-wellcell culture plates. After overnight incubation at 37° C. 5% CO2, cellswere treated with compounds and vehicle at 37° C. for 2 hours.Thereafter, cells were lysed in 150 μl lysis buffer and the levels ofphospho-AKT at T308 and S473 and p-4E-BP1 at T70 sites were determinedwith the corresponding AlphaScreen® SureFire® assay kits (Perkin Elmer:4E-BP1 Assay Kit Cat # TRG4E2S10K; Akt 1/2/3 p-Ser 473 #TGRA4S500 andAkt 1/2/3 p-Thr 308 #TGRA3S500 as well as IgG detection Kit #6760617M)as described in the manuals. All measurements where at least done induplicates and confirmed by independent repetition.

Alternatively pAKT-S473 was measured using the “Akt Duplex” of theMULTI-SPOT® Assay System (Fa. Meso Scale Discovery, Cat# N41100B-1)following manufacturers instructions. Each assay used 20 μg of proteinextract and measured total AKT and p-AKT content simultaneously in onewell. All measurements where at least done in duplicates and confirmedby independent repetition. Values for P-AKT are expressed as percentageof P-AKT level compared to total-AKT content of the extracts.

The following Table gives selected data for selected Examples of thepresent invention.

pAKT-S743 median Example IC₅₀, μM 1-0 not tested 1-1 10.00 2-0 nottested 3-0 1.55 4-0 not tested 4-1 not tested 4-2 not tested 4-3 nottested 4-4 not tested 4-5 0.03 4-6 0.03 4-7 0.16 4-8 0.11 4-9 0.04  4-100.07  4-11 0.02  4-12 0.01  4-13 0.16  4-14 0.92  4-15 0.00  4-16 nottested  4-17 0.06  4-18 0.00 5-0 10.00 5-1 10.00 5-2 10.00 5-3 9.17 5-410.00 5-5 4.11 5-6 10.00 6-0 0.41 7-0 0.61 8-0 0.05 9-0 0.03 10-0  10.0011-0  10.00 12-0  10.00 13-0  10.00

Biological Assay 4.0 Tumor Cell Proliferation Assays

Compounds were tested in a cell-based assay that measures the capacityof the compounds to inhibit tumour cell proliferation following a 72 hdrug exposure. Cell viability is determined using CellTiter-Glow® (CTG,Promega, cat# G757112/3). The CellTiter-Glo® Luminescent Cell ViabilityAssay is a homogeneous method to determine the number of viable cells inculture. Detection is based on using the luciferase reaction to measurethe amount of ATP from viable cells. The amount of ATP in cellscorrelates with cell viability. Within minutes after a loss of membraneintegrity, cells lose the ability to synthesize ATP, and endogenousATPases destroy any remaining ATP; thus the levels of ATP fallprecipitously.

Cells were plated at 3000-5000 cells/well (depending on the cell lines)in 90 μL growth medium on MTPs (Corning; #3603, black plate, clear flatbottom). For each cell line assayed, cells were plated onto a separateplate for determination of fluorescence at t=0 hour and t=72 hour timepoints. Following overnight incubation at 37° C., chemiluminescencevalues for the t=0 samples were determined after adding 10 μl medium and100 μl CTG solution according to manufacture protocol. Plates for thet=72 hour time points were treated with compounds diluted into growthmedium at ten times final concentration added in 10 μL to the cellculture plate. Cells were then incubated for 72 hours at 37° C.Chemiluminescence values for the t=72 hour samples were determined. Fordata analysis, briefly, data from 24 h plate where used to reflect 100%inhibition of growth (“Ci”) and DMSO control for uninhibited growth(“C0”) and analyzed using MTS software package for IC₅₀ and Hillcoefficient. Experiments were controlled using a reference compound asstandard.

The following Table gives selected data for selected Examples of thepresent invention.

KPL-4 proliferation Example IC₅₀, μM 1-0 3.54 1-1 10.00 2-0 not tested3-0 1.71 4-0 1.85 4-1 2.03 4-2 2.56 4-3 1.91 4-4 6.00 4-5 1.31 4-6 1.594-7 1.75 4-8 2.38 4-9 1.56  4-10 1.26  4-11 1.41  4-12 0.55  4-13 3.36 4-14 6.02  4-15 1.40  4-16 5.17  4-17 6.20  4-18 1.81 5-0 3.85 5-1 2.115-2 2.75 5-3 2.28 5-4 2.38 5-5 3.69 5-6 9.22 6-0 1.89 7-0 3.03 8-0 2.429-0 1.87 10-0  2.49 11-0  5.28 12-0  3.20 13-0  2.47

Example 5.0 Caco2 Permeability Assay

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded ata density of 4.5×10⁴ cell per well on 24 well insert plates, 0.4 μm poresize, and grown for 15 days in DMEM medium supplemented with 10% fetalbovine serum, 1% GlutaMAX (100×, GIBCO), 100 U/ml penicillin, 100 μg/mlstreptomycin (GIBCO) and 1% non essential amino acids (100×). Cells weremaintained at 37° C. in a humified 5% CO₂ atmosphere. Medium was changedevery 2-3 day. Before running the permeation assay, the culture mediumwas replaced by a FCS-free hepes-carbonate transport puffer (pH 7.2) Forassessment of monolayer integrity the transepithelial electricalresistance (TEER) was measured. Test compounds were predissolved in DMSOand added either to the apical or basolateral compartment in finalconcentration of 2 μM. Before and after 2 h incubation at 37° C. sampleswere taken from both compartments. Analysis of compound content was doneafter precipitation with methanol by LC/MS/NAS analysis. Permeability(Papp) was calculated in the apical to basolateral (A→B) and basolateralto apical (B→A) directions. The apparent permeability was calculatedusing following equation:

P _(app)=(V _(r) /P _(o))(1/S)(P ₂ /t)

Where V_(r) is the volume of medium in the receiver chamber; P_(o) isthe measured peak area of the test drug in the donor chamber at t=0, Sthe surface area of the monolayer, P₂ is the measured peak area of thetest drug in the acceptor chamber after 2 h of incubation, and t is theincubation time. The efflux ratio basolateral (B) to apical (A) wascalculated by dividing the P_(app) B-A by the P_(app) A-B. In additionthe compound recovery was calculated. As assay control referencecompounds were analyzed in parallel.

Example 6.0 In Vivo Rat Pharmacokinetics

For in vivo pharmacokinetic experiments test compounds were administeredto male Wistar rats intravenously at doses of 0.3 to 1 mg/kg andintragastral at doses of 0.6 to 10 mg/kg formulated as solutions usingsolubilizers such as PEG400 in well-tolerated amounts.

For pharmacokinetics after intravenous administration test compoundswere given as i.v. bolus and blood samples were taken at 2 min, 8 min,15 min, 30 min. 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing.Depending on the expected half-life additional samples were taken atlater time points (e.g. 48 h, 72 h). For pharmacokinetics afterintragastral administration test compounds were given intragastral tofasted rats and blood samples were taken at 5 min, 15 min, 30 min, 45min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing. Depending on theexpected half-life additional samples were taken at later time points(e.g. 48 h, 72 h). Blood was collected into Lithium-Heparintubes(Monovetten® Sarstedt) and centrifuged for 15 min at 3000 rpm. Analiquot of 100 μL from the supernatant (plasma) was taken andprecipitated by addition of 400 μL cold acetonitrile and frozen at −20°C. over night. Samples were subsequently thawed and centrifuged at 3000rpm, 4° C. for 20 minutes. Aliquots of the supernatants were taken foranalytical testing using an Agilent 1200 HPLC-system with LCMS/MSdetection. PK parameters were calculated by non-compartmental analysisusing a PK calculation software.

PK parameters derived from concentration-time profiles after i.v.:CLplasma: Total plasma clearance of test compound (in L/kg/h); CLblood:Total blood clearance of test compound: CLplasma*Cp/Cb (in L/kg/h) withCp/Cb being the ratio of concentrations in plasma and blood. PKparameters calculated from concentration time profiles after i.g.: Cmax:Maximal plasma concentration (in mg/L); Cmaxnorm: Cmax divided by theadministered dose (in kg/L); Tmax: Time point at which Cmax was observed(in h). Parameters calculated from both, i.v. and i.g.concentration-time profiles: AUCnorm: Area under the concentration-timecurve from t=0 h to infinity (extrapolated) divided by the administereddose (in kg*h/L); AUC(0−tlast)norm: Area under the concentration-timecurve from t=0 h to the last time point for which plasma concentrationscould be measured divided by the administered dose (in kg*h/L); t½:terminal half-life (in h); F: oral bioavailability: AUCnorm afterintragastral administration divided by AUCnorm after intravenousadministration (in %).

The person skilled in the art will be aware of methods to show in vivoefficacy of anti-cancer compounds. By way of illustration, the followingexample describes methods of quantifying the in vivo efficacy in a mousexenograft model. The skilled person will be able to apply suchprinciples to derive models from alternative tumor material.

Example 7.0 In Vivo Xenograft Mechanism of Action Study

To demonstrate that compounds act in tumours by the anticipated mode ofaction phosphorylation of the AKT protein was investigated in PC3prostate tumours treated once with 50 mg/kg compound.

To this extent PC3 human prostate tumours were xenografted onto athymicnude mice. PC3 tumour cells were cultivated according to ATCC protocolsin recommended media contained 10% FCS and harvested for transplantationin a subconfluent (70%) state. 3×10⁶ tumour cells suspended in 50%Matrigel were subcutaneously implantated into the inguinal region ofmale mice. Tumours were allowed to grow to the predetermined size of60-80 mm². When the tumours were approximately in size, the animals wererandomized to treatment and control groups (groups size: 9 animals) andtreatment was started. Animals were treated once with 50 mg/kg compoundor vehicle per oral administration (p.o.) carried out via a gastrictube. Treatment of each animal was based on individual body weight. At2, 5 and 24 hours post treatment 3 animals each were sacrificed and thePC3 tumours excised. Tumour samples of approximately 5×5×5 mm were lysedon ice in MSD lysis buffer in the presence of protease and phosphataseinhibitors using Tissue Lyzer (Qiagen, Germany). The levels of p-AKTS473 in extracts from tumour tissue were analysed in an ELISA basedassay. This assay is based on the “Akt Duplex” of the MULTI-SPOT® AssaySystem (Fa. Meso Scale Discovery, Cat# N41100B-1) followingmanufacturers instructions. Each assay used 20 μg of protein extract andmeasured total AKT and p-AKT content simultaneously in one well. Allmeasurements where at least done in duplicates and confirmed byindependent repetition. Values for P-AKT are expressed as percentage ofP-AKT level compared to total-AKT content of the extracts. Vehicletreated tumours were analyzed to determine the basal level of P-AKT inthis model and used as a normalization control to determine the % P-AKTrelative to vehicle levels.

Preferred compounds of the present invention show in this assay:relative to vehicle levels P-AKT <30% at 2 hours post treatment, morepreferably at 5 hours post treatment, even more preferably at 24 hourspost treatment.

Example 7.1 In Vivo Xenograft Efficacy Study

To determine the therapeutic efficacy and tolerability of compounds,tumour growth of PC3 prostate tumours xenografted onto nude mice may beobserved. Mice were treated either with vehicle or compounds.

To this extent PC3 xenografts were established as described above.Tumours were allowed to grow to the predetermined size of 25-35 mm².When the tumours were approximately in size, the animals were randomizedto treatment and control groups (groups size: 8 animals) and treatmentwas started. Treatment of each animal was based on individual bodyweight and oral administration (p.o.) was carried out via a gastrictube. The oral application volumes were 10 ml/kg for mice. Mice weretreated once daily with 50 mg/kg compounds.

Tumour response was assessed by determination of the tumour area(product of the longest diameter and its perpendicular) using acalliper. The animal body weight was monitored as a measure fortreatment-related toxicity. Measurement of tumour area and body weightwere performed 2-3 times weekly. Statistical analysis was assessed usingthe SigmaStat software. A one way analysis of variance was performed,and differences to the control were compared by a pair-wise comparisonprocedure (Dunn's method). T/C ratios (Treatment/Control) werecalculated with final tumour weights at study end.

1. A compound of formula (I)

wherein R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2,2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl,2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl, wherein said groupbeing optionally substituted, one or more times, identically ordifferently, with a substituent selected from: hydroxy, halogen,1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9,cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)₂R11, —S(O)₂R11,—S(O)₂NR8R9, R2 is hydrogen, halogen, cyano, or a group selected from1-6C-alkyl, 3-7C-cycloalkyl, wherein said 1-6C-alkyl being optionallysubstituted, one or more times, identically or differently, with asubstituent selected from: hydroxy, halogen, 1-6C-alkoxy, R3 ishydrogen, 1-6C-alkyl, 3-7C-cycloalkyl, R4 is phenyl optionallysubstituted, one or more times, identically or differently, with asubstituent selected from: 1-6C-alkyl, halogen, cyano, R5 is hydrogen,halogen, R6 is hydrogen, 1-6C-alkyl, R8, R9 which can be the same ordifferent, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same wayof differently one or more times with halogen, hydroxy, mono- ordi-1-4C-alkylamino, 1-4C-alkoxy, or, in the case of —NR8R9, R8 and R9together with the nitrogen to which they are attached may also form a3-6C-heterocyclic ring, R10 is hydrogen, 1-6C-alkyl, R11 is 1-4C-alkyl(optionally substituted in the same way of differently one or more timeswith halogen, hydroxy) or 3-7C-cycloalkyl, X is —(CH₂)_(n)—, n is 0, 1,2, or 3, Y is —CH₂—, —CH(OH)—, or an N-oxide, a salt, a tautomer or astereoisomer of said compound, or a salt of said N-oxide, tautomer orstereoisomer.
 2. A compound according to claim 1, wherein R1 ishydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or agroup selected from 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl,heteroaryl, wherein said group being optionally substituted, one or moretimes, identically or differently, with a substituent selected from:hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,—NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9, R2 is hydrogen, halogen, cyano, ora group selected from 1-6C-alkyl, 3-7C-cycloalkyl, wherein said1-6C-alkyl being optionally substituted, one or more times, identicallyor differently, with a substituent selected from: hydroxy, halogen,1-6C-alkoxy, R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl, R4 is phenyloptionally substituted, one or more times, identically or differently,with a substituent selected from: 1-6C-alkyl, halogen, cyano, R5 ishydrogen, halogen, R6 is hydrogen, R8, R9 which can be the same ordifferent, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same wayof differently one or more times with halogen, hydroxy, mono- ordi-1-4C-alkylamino, 1-4C-alkoxy, or, in the case of —NR8R9, R8 and R9together with the nitrogen to which they are attached may also form a3-6C-heterocyclic ring, R10 is hydrogen, 1-6C-alkyl, R11 is 1-4C-alkyl(optionally substituted in the same way of differently one or more timeswith halogen, hydroxy) or 3-7C-cycloalkyl, X is (CH₂)_(n)—, n is 0, 1,2, or 3, Y is —CH₂—, —CH(OH)—, or an N-oxide, a salt, a tautomer or astereoisomer of said compound, or a salt of said N-oxide, tautomer orstereoisomer.
 3. A compound according to claim 1, wherein R1 ishydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or agroup selected from 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl,heteroaryl, wherein said group being optionally substituted, one or moretimes, identically or differently, with a substituent selected from:hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl,1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,—NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9, R2 is hydrogen, halogen, cyano, ora group selected from 1-6C-alkyl, 3-7C-cycloalkyl, R3 is hydrogen,1-6C-alkyl, 3-7C-cycloalkyl, R4 is phenyl, R5 is hydrogen, R6 ishydrogen, R8, R9 which can be the same or different, is hydrogen,1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and3-7C-cycloalkyl is optionally substituted in the same way of differentlyone or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino,1-4C-alkoxy, or, in the case of —NR8R9, R8 and R9 together with thenitrogen to which they are attached may also form a 3-6C-heterocyclicring, R10 is hydrogen, 1-6C-alkyl, R11 is 1-4C-alkyl (optionallysubstituted in the same way of differently one or more times withhalogen, hydroxy) or 3-7C-cycloalkyl, X is (CH₂)_(n)—, n is 0, 1, 2, or3, Y is —CH₂—, —CH(OH)—, or an N-oxide, a salt, a tautomer or astereoisomer of said compound, or a salt of said N-oxide, tautomer orstereoisomer.
 4. A compound according to claim 1, wherein R1 ishydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or agroup selected from 1-6C-alkyl, 2-6C-alkenyl, aryl, heteroaryl, whereinsaid group being optionally substituted, one or more times, identicallyor differently, with a substituent selected from: hydroxy, halogen,1-6C-alkyl, 1-4C-hydroxyalkyl, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,—NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9, R2 is hydrogen, halogen, cyano, or1-6C-alkyl, R3 is hydrogen, R4 is phenyl, R5 is hydrogen, R6 ishydrogen, R8, R9 which can be the same or different, is hydrogen,1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and3-7C-cycloalkyl is optionally substituted in the same way of differentlyone or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino,1-4C-alkoxy, or, in the case of —NR8R9, R8 and R9 together with thenitrogen to which they are attached may also form a 3-6C-heterocyclicring, R10 is hydrogen, 1-6C-alkyl, R11 is 1-4C-alkyl, X is (CH₂)_(n)—, nis 1, Y is —CH₂—, or an N-oxide, a salt, a tautomer or a stereoisomer ofsaid compound, or a salt of said N-oxide, tautomer or stereoisomer.
 5. Acompound according to claim 1, wherein, R1 is hydrogen, halogen,1-3C-alkyl, 2-3C-alkenyl, —(CH═CH)C(O)NH2, —(CH═CH)C(O)OR10, pyrazolyl(optionally substituted with methyl), pyridyl (optionally substitutedwith hydroxy, methoxy, —C(O)OR10), indazolyl, phenyl, wherein the phenylgroup can optionally be substituted with a substituent selected from thegroup consisting of halogen, methyl, hydroxymethyl, cyano, C(O)NH₂,—C(O)OR10, —S(O)₂R11, SO₂—NH₂, R2 is hydrogen, methyl, halogen, R3 ishydrogen, R4 is phenyl, R5 is hydrogen, R6 is hydrogen, R10 is1-3C-alkyl, R11 is 1-3C-alkyl, X is —CH₂—, Y is —CH₂—, or an N-oxide, asalt, a tautomer or a stereoisomer of said compound, or a salt of saidN-oxide, tautomer or stereoisomer.
 6. A compound according to claim 1,which is selected from the group consisting of:1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,1-{4-[3-(4-Methanesulfonylphenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzoicacid methyl ester,1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,1-[4-(7-Phenyl-3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,(3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol,(4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanolformiate,4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzenesulfonamidehydrochloride,1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylaminehydrochloride,(5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanolhydrochloride,4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamidehydrochloride,3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamidehydrochloride,1-{4-[7-Phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylaminehydrochloride.5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridin-2-ol,5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridine-2-carboxylicacid methyl ester,1-{4-[7-Phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,1-{4-[3-(1H-Indazol-6-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-nicotinicacid ethyl ester,1-{4-[3-(5-Methoxypyridin-3-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,(5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol,1-{4-[2-Methyl-7-phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,1-{4-[3-(4-Fluorophenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,1-{4-[2-Methyl-7-phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,1-{4-[2-Methyl-7-phenyl-3-(5-methyl-2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,1-[4-(7-Phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylicacid methyl ester,1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,1-[4-(3-Ethyl-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine.7. A compound of formula (II),

wherein Rx is R6 or a protecting group, Ry is hydrogen or a protectinggroup, whereby Rx and Ry together, or Y and Rx together, may form acyclic protecting group, R1 is hydrogen, halogen,2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selectedfrom 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from: hydroxy,halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy,—NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)₂R11,—S(O)₂R11, —S(O)₂NR8R9, R2 is hydrogen, halogen, cyano, or a groupselected from 1-6C-alkyl, 3-7C-cycloalkyl, wherein said 1-6C-alkyl beingoptionally substituted, one or more times, identically or differently,with a substituent selected from: hydroxy, halogen, 1-6C-alkoxy, R3 ishydrogen, 1-6C-alkyl, 3-7C-cycloalkyl, R4 is phenyl optionallysubstituted, one or more times, identically or differently, with asubstituent selected from: 1-6C-alkyl, halogen, cyano, R5 is hydrogen,halogen, R6 is hydrogen, 1-6C-alkyl, R8, R9 which can be the same ordifferent, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same wayof differently one or more times with halogen, hydroxy, mono- ordi-1-4C-alkylamino, 1-4C-alkoxy, or, in the case of —NR8R9, R8 and R9together with the nitrogen to which they are attached may also form a3-6C-heterocyclic ring, R10 is hydrogen, 1-6C-alkyl, R11 is 1-4C-alkyl(optionally substituted in the same way of differently one or more timeswith halogen, hydroxy) or 3-7C-cycloalkyl, X is (CH₂)_(n)—, n is 0, 1,2, or 3, and Y is —CH₂—, —CH(OH)—.
 8. (canceled)
 9. (canceled)
 10. Amethod for the treatment or prophylaxis of a hyperproliferative diseaseor disorder responsive to induction of apoptosis comprisingadministering to a human in need thereof an effective amount of acompound according to claim
 1. 11. The method according to claim 10,wherein the hyperproliferative disease and/or disorder responsive toinduction of apoptosis is a benign or malignant neoplasm.
 12. Apharmaceutical composition comprising at least one compound according toclaim 1, together with at least one pharmaceutically acceptableauxiliary.
 13. (canceled)
 14. A pharmaceutical combination comprising atleast one compound according to claim 1, and one or more second activeingredients selected from chemotherapeutic anti-cancer agents andtarget-specific anti-cancer agents.
 15. (canceled)
 16. A compoundaccording to claim 2, wherein R1 is hydrogen, halogen,2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selectedfrom 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,wherein said group being optionally substituted, one or more times,identically or differently, with a substituent selected from: hydroxy,halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy,—NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)₂R11,—S(O)₂R11, —S(O)₂NR8R9, R2 is hydrogen, halogen, cyano, or a groupselected from 1-6C-alkyl, 3-7C-cycloalkyl, R3 is hydrogen, 1-6C-alkyl,3-7C-cycloalkyl, R4 is phenyl, R5 is hydrogen, R6 is hydrogen, R8, R9which can be the same or different, is hydrogen, 1-4C-alkyl or3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl isoptionally substituted in the same way of differently one or more timeswith halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy, or, inthe case of —NR8R9, R8 and R9 together with the nitrogen to which theyare attached may also form a 3-6C-heterocyclic ring, R10 is hydrogen,1-6C-alkyl, R11 is 1-4C-alkyl (optionally substituted in the same way ofdifferently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,X is (CH₂)_(n)—, n is 0, 1, 2, or 3, Y is —CH₂—, —CH(OH)—, or anN-oxide, a salt, a tautomer or a stereoisomer of said compound, or asalt of said N-oxide, tautomer or stereoisomer.
 17. A compound accordingto claim 2, wherein R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2,2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl,2-6C-alkenyl, aryl, heteroaryl, wherein said group being optionallysubstituted, one or more times, identically or differently, with asubstituent selected from: hydroxy, halogen, 1-6C-alkyl,1-4C-hydroxyalkyl, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11,—NHS(O)₂R11, —S(O)₂R11, —S(O)₂NR8R9, R2 is hydrogen, halogen, cyano, or1-6C-alkyl, R3 is hydrogen, R4 is phenyl, R5 is hydrogen, R6 ishydrogen, R8, R9 which can be the same or different, is hydrogen,1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and3-7C-cycloalkyl is optionally substituted in the same way of differentlyone or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino,1-4C-alkoxy, or, in the case of —NR8R9, R8 and R9 together with thenitrogen to which they are attached may also form a 3-6C-heterocyclicring, R10 is hydrogen, 1-6C-alkyl, R11 is 1-4C-alkyl, X is (CH₂)_(n)—, nis 1, Y is —CH₂—, or an N-oxide, a salt, a tautomer or a stereoisomer ofsaid compound, or a salt of said N-oxide, tautomer or stereoisomer. 18.A compound according to claim 2, wherein, R1 is hydrogen, halogen,1-3C-alkyl, 2-3C-alkenyl, —(CH═CH)C(O)NH2, —(CH═CH)C(O)OR10, pyrazolyl(optionally substituted with methyl), pyridyl (optionally substitutedwith hydroxy, methoxy, —C(O)OR10), indazolyl, phenyl, wherein the phenylgroup can optionally be substituted with a substituent selected from thegroup consisting of halogen, methyl, hydroxymethyl, cyano, C(O)NH₂,—C(O)OR10, —S(O)₂R11, SO₂—NH₂, R2 is hydrogen, methyl, halogen, R3 ishydrogen, R4 is phenyl, R5 is hydrogen, R6 is hydrogen, R10 is1-3C-alkyl, R11 is 1-3C-alkyl, X is —CH₂—, Y is —CH₂—, or an N-oxide, asalt, a tautomer or a stereoisomer of said compound, or a salt of saidN-oxide, tautomer or stereoisomer.